Salts of heterocyclic modulators of HIF activity for treatment of disease

ABSTRACT

The present disclosure relates to salts of heterocyclic compounds and methods that inhibit HIF pathway activity. The compounds are designed to treat or prevent cancer and other hypoxia-mediated diseases.

This application claims the benefit of priority of U.S. ProvisionalApplication No. 61/944,345, filed Feb. 25, 2014, the disclosure of whichis hereby incorporated by reference as if written herein in itsentirety.

The present disclosure relates to heterocyclic compounds, compositions,and methods to inhibit HIF pathway activity, more specifically tomethods for treating diseases mediated by HIF pathway activity.

The heterodimeric HIF transcription factor is composed of a stable HIF1β(aka ARNT) and an oxygen regulatable HIFα subunit (HIF1α or EPAS1 (akaHIF2α) (Semenza, 2012b). Under normal physiological conditions, thecapacity of the cell to degrade the HIFα subunits exceeds the amount ofHIFα protein that is being synthesized. The HIFα subunit is regulated byhydroxylation at two key proline residues (i.e. Pro⁴⁰² and Pro⁵⁶⁴ inHIF1α) by a family of proline hydroxylases (PHD1, PHD2 and PHD3), thatutilize α-ketoglutarate and oxygen as substrates to generatehydroxylated HIFα, succinate and CO₂ (Kaelin and Ratcliffe, 2008).Hydroxylation of HIFα makes it a substrate for the VHL ubiquitin ligasecomplex, which promotes HIFα polyubiquitination, thus targeting HIFα forproteosomal degradation. This process is very rapid at normal oxygenlevels, with a <5 minute half-life of HIFα protein, thus enabling rapidregulation of the complex and HIF activity in response to changes inoxygen levels (Maxwell et al., 1999).

Frequently in disease, the HIF pathway is activated by either reducedoxygen levels or genetic alterations that increase the amount ofstabilized HIFα subunit (Semenza, 2012a). Increased HIFα levels occurthrough several mechanisms that include increased in HIFα subunit mRNAexpression, HIFα protein translation, or through a decrease in HIFαprotein degradation. Increased HIF leads to several biological pathwaysbeing activated through HIF mediated transcription of genes that promotestem cell maintenance, metabolic reprogramming, endothelial tomesenchymal transition (EMT), survival, proliferation, migration, pHregulation and angiogenesis.

A substantial body of preclinical experimentation and clinical evidencehas implicated HIF as an important therapeutic target that is essentialfor the maintenance of a subset of tumors and a potential majorcontributor to therapeutic resistance and residual disease (Kaelin,2011; Kaelin and Ratcliffe, 2008; Li et al., 2005; Semenza, 2012a;Semenza, 2012b). In numerous clinical studies, tumor hypoxia has beenreported to correlate with poor prognosis and incomplete response tocurrent therapeutic agents, including various chemotherapies as well asradiotherapy (Harada et al., 2012; Rohwer and Cramer, 2011; Wilson andHay, 2011). This is most likely due to HIF regulation of procancerousmechanisms, including increased proliferation, activation of survivalpathways such as autophagy, enhanced glycolysis as part of a metabolicreprogramming shift away from oxidative phosphorylation, increasedmigration/invasion promoting metastasis, maintenance of pluripotent“stem cell” population and stimulation of angiogenesis through thesynthesis and secretion of pro-angiogenic growth factors.

The loss of any of several tumor suppressors (i.e. VHL, SDH, FH, TSC andothers) and/or dysregulation of several oncogenic pathways (i.e. RAS andPi3K) activate the HIF pathway and its downstream effector pathways, butdo so in the presence of oxygen creating a “pseudohypoxic” state. Thesesubsets of tumors become dependent on the HIF pathway for theircontinued growth. An example of a genetically driven HIF tumorindication is renal cell carcinoma (RCC), in which the tumor suppressorVHL is inactivated by mutation, deletion or promoter hypermethylation in70% of tumors (Kim and Kaelin, 2004). VHL inactivation results in HIFαstabilization that is independent of oxygen concentration. In anotherexample, tumors where either fumarate hydratase (FH) or a subunit in thesuccinate dehydrogenase (SDH) complex is inactivated, HIFα accumulationoccurs due to inhibition of PHDs by succinate and fumarate (Bardella etal., 2011; Gill, 2012; Isaacs et al., 2005; Pollard et al., 2005). Thelack of HIFα hydroxylation prevents VHL mediated degradation.

In other tumors, the Pi3K pathway is frequently mutated (i.e., PTENloss, AKT, PIK3CA, TSC1/2, LKB1 and others) ultimately leading to anincrease in the activity of mammalian target of rapamycin (mTOR), whichresults in an increase in HIFα protein translation to the point where itoverwhelms the degradation pathway. Therefore, in tumors with activePi3K pathway, HIF pathway activity is frequently increased (Wouters andKoritzinsky, 2008). Taken together, in tumors where the HIF pathway isdriven by specific genetic changes, therapeutic interventions thatinactivate the HIF pathway in genetically driven HIF dependent tumorsmay provide substantial therapeutic benefit as monotherapy or as part ofa combination therapy.

In addition to the activation of HIF through genetic alterations, HIF isalso activated in hypoxia that results from the tumor outgrowing thevasculature as well as a result of therapeutic intervention. HIFmediated survival of cells in hypoxia is a major contributor toresistance to therapies, lack of durable response and the foundation ofresidual disease. When tumor cells become hypoxic, several HIF dependentmechanisms prolong the survival of the cells in the harsh nutrient andoxygen deprived environment. These include genomic instability topromote adaptation (Klein and Glazer, 2010; Koi and Boland, 2011),metabolic reprogramming, induction of autophagy to recycle energy(Mazure and Pouyssegur, 2010), secretion of pro-angiogenic factors topromote neovascularization and cessation of pro-growth pathways. Severehypoxia mediates innate resistance to radiotherapy and chemotherapy,which require oxygen and proliferation, respectively, as part of theirmechanisms of action. Alternatively, resistance can be adaptive as inthe case of anti-angiogenic therapies, such as anti-VEGF therapies, thatcreate hypoxic niches due to the destruction of the vasculature, whichcreates more intratumoral hypoxia thus activating HIF and promoting itsmilieu of procancerous pathways. Multiple reports in mouse models ofcancer show that treatment with an anti-VEGF therapy promotedmetastasis, most likely through HIF mediated activation of tumor cellmigration/invasion (Ebos et al., 2009; Paez-Ribes et al., 2009). Hypoxiahas also been proposed to promote genomic alteration by increasing DNAdamage, including impairment of mismatch repair, nucleotide excisionrepair, double strand break repair and homologous recombination repair.The introduction of point mutations, frameshifts, insertions, deletions,amplifications and translocations give rise to tumor heterogeneity andevolution that provide the genetic alterations that enable adaptiveresistance of tumors.

In most tumor types, inhibition of the HIF pathway activity willsensitize tumors to standard of care therapies such as anti-angiogenictherapies, radiotherapies, chemotherapies and targeted therapies byeither improving the perfusion of drug and oxygen throughout the tumorvia normalization of vascular function (Carmeliet and Jain, 2011;Chauhan et al., 2012) and by directly targeting the resistant HIFactivated tumor cells to inhibit HIF mediated survival pathways.

In addition to cancer, inactivation of HIF pathway would be beneficialfor conditions where activation of HIF promotes the disease statethrough aberrant survival or through promotion of neovascularization.These include traumatic shock, pulmonary arterial hypertension,obstructive sleep apnea, cardiovascular diseases such as cardiacarrhythmia and heart failure, diseases that involve neoangiogenesis suchas ocular macular degeneration and rheumatoid arthritis, sepsis andinflammation and diseases of the lung and kidney where fibrosis occursdue HIF mediated EMT (Arjamaa et al., 2009; Semenza, 2012a; Westra etal., 2010).

To date, numerous small molecules have been reported that down regulatethe HIF pathway via several direct and indirect mechanisms which targetvarious HIF intervention points (Jones and Harris, 2012; Poon et al.,2009; Semenza, 2012b). These include reducing HIFα mRNA, reducing HIFαprotein translation, reducing reactive oxygen species (ROS), increasingHIFα degradation, disrupting HIFα/HIF1β dimerization or the HIFαinteraction with p300, a co-factor for HIF translation. Genetic andpharmacological inhibition of the HIF pathway utilizing RNAi, geneticablation or via small molecule inhibitors have been reported to reducethe growth of tumors in preclinical models clearly establishing that theHIF pathway performs a critical function in tumor growth and maintenance(Onnis et al., 2009). Hence, promoting HIFα degradation as part of atherapeutic intervention regime would be highly beneficial to patients.

Thus, there remains a need for compounds and methods for inhibiting HIFpathway activity.

Accordingly, the inventors herein disclose a series of heterocycliccompounds that inhibit HIF pathway activity and promote VHL and PHDmediated degradation of HIF. These compounds provide improved oralbioavailability

Provided is a compound of structural Formula I(R₁)_(n)-A-Y₁—B-D-E-(R₃)_(p).(M)_(a).(H₂O)_(b)   (I)wherein: M is selected from the group consisting of an inorganic acid,an organic acid, an amino acid; with the proviso that M is nottrifluoroacetic acid; a is a fractional or whole number between about0.5 and about 3.5 inclusive; b is a fractional or whole number betweenabout 0 and about 10 inclusive; n is 0, 1, or 2; p is 0, 1, or 2; q is0, 1, 2, 3, or 4; u is 0, 1, or 2; A is aryl or heteroaryl; B is

D is alkyl, heteroalkyl, alkoxy, alkylthio, carbonyl, alkylcarbonyl,carboxyl, oxy, thio, sulfinyl, sulfonyl, sulfonamido, amino, amido,alkylamino, or heteroaryl, any of which can be optionally substitutedwith one or more substituents hydrogen, deuterium, halogen, alkyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, or oxo, any of which may be optionallysubstituted; E is aryl or heteroaryl; G is saturated 3- to 7-memberedcycloalkyl or saturated 3- to 7-membered heterocycloalkyl; R₁ is—Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium, halogen, alkyl, alkenyl,alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl,acyl, carboxylalkyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, thiolalkyl, mercaptyl, thiol,sulfonate, sulfonamido, alkylsulfonyl, amino, amido, alkylamino,dialkylamino, carbamate, nitro, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl,heteroarylcarbonyl, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl,heterocycloalkylcarbonylalkyl, or heteroarylalkyl, any of which can beoptionally substituted with one or more substituents hydrogen,deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, amidoalkyl, acyl, carbonyl, carboxyl,carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl, hydroxyalkylcarbonyl,aminoalkylcarbonyl, alkylaminoalkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, thiol, acylthio, sulfonamido,alkylsulfonyl, amino, amido, carbamate, alkylamino, dialkylamino,alkylaminoalkyl, dialkylaminoalkyl, nitro, trisubstituted silyl,trisubstituted siloxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,alkylheterocycloalkyl, any of which may be optionally substituted; R₃ ishydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acyl, carbonyl,carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio, mercaptyl, thiol,haloalkylthio, perhaloalkylthio, cyanoalkylthio, haloalkylsulfonyl,alkylsulfonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl, sulfonate,sulfonamido, amino, amido, alkylamino, dialkylamino, carbamate, nitro,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, or heteroarylalkyl, trisubstituted silyl, —SF₅,—(C(R₃₁)(R₃₂))_(q)—O-alkyl, —(C(R₃₁)(R₃₂))_(q)—O-cycloalkyl,—S(O)_(u)-alkyl, —S(O)_(u)-cycloalkyl, cycloalkylthio, —CF₃, —OCF₃,—(C(R₃₁)(R₃₂))_(q)—OCF₃, saturated heterocycloalkyloxy,—(C(R₃₁)(R₃₂))_(q)—O-saturated heterocycloalkyl, —(C(R₃₁)(R₃₂))_(u)—saturated heterocycloalkyl, saturated heterocycloalkylthio,—S(O)_(u)-saturated heterocycloalkyl, —(C(R₃₁)(R₃₂))_(q)—OCF₃,

any of which may be optionally substituted; R₄ and R₅ are independentlyhydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl, alkoxy, haloalkoxy,perhaloalkoxy, alkylsulfonyl, sulfonamido, amido, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, or heteroarylalkyl, or R₄ and R₅, taken together,form a heterocyloalkyl or heteroaryl, any of which can be optionallysubstituted with one or more substituents hydrogen, deuterium, halogen,alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, mercaptyl, thiol, sulfonate,sulfonamido, amino, amido, alkylamino, dialkylamino, carbamate, nitro,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, or heteroarylalkyl, any of which may beoptionally substituted; each R₂₃ is independently hydrogen, deuterium,halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,aminoalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, amino, alkylamino,dialkylamino, nitro, cycloalkyl, aryl, or heteroaryl, any of which maybe optionally substituted; R₃₁, R₃₂, R₃₃, R₃₄, or R₃₆ are independentlyhydrogen, deuterium, alkyl, or perfluoroalkyl, any of which can beoptionally substituted; R₃₅ is hydrogen, deuterium, alkyl,perfluoroalkyl, cycloalkyl, or saturated heterocycloalkyl, any of whichcan be optionally substituted; R₃₇ or R₃₈ are independently alkyl orperfluoroalkyl, or R₃₇ and R₃₈, taken together, form a heterocyloalkyl,any of which can be optionally substituted; Y₁ is alkyl, alkenyl,alkynyl, heteroalkyl, alkoxy, alkylthio, carbonyl, alkylcarbonyl,carboxyl, oxy, thio, sulfinyl, sulfonyl, sulfonamido, amino, amido,alkylamino, or carbamate, any of which can be optionally substitutedwith one or more substituents hydrogen, deuterium, halogen, alkyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl,carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, alkylthio, amino, alkylamino, dialkylamino, or cycloalkyl, any ofwhich may be optionally substituted; Y₂ is a bond, carbonyl,alkylcarbonyl, carboxyl, oxy, thio, sulfinyl, sulfonyl, sulfonamido,amino, amido, alkylamino, or carbamate, any of which can be optionallysubstituted with one or more substituents hydrogen, deuterium, halogen,alkyl, alkenyl, alkynyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, mercaptyl, thiol, sulfonate,sulfonamido, amino, amido, alkylamino, dialkylamino, carbamate,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy, cycloalkylalkyl, arylalkyl,heterocycloalkylalkyl, or heteroarylalkyl, any of which may beoptionally substituted; if A is phenyl, B is not

wherein Q₂ or Q₃ are freely substituted; if A is phenyl or pyridyl, Y₁is CH₂, B is

and Q₁ is methyl, ethyl, or trifluoromethyl, then D is not

and wherein * represents the point of attachment to Y₁ and ** representsthe point of attachment to D, and # represents the point of attachmentto B and ## represents the point of attachment to E.

Provided is a compound selected from the group consisting of:5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride;5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole2,2,2-trifluoroacetate;5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemethanesulfonate; or5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolebenzenesulfonate.

Provided is a method of treatment of a HIF pathway-mediated diseasecomprising the administration of a therapeutically effective amount of acompound as disclosed herein to a patient in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1—Compounds of this disclosure inhibit the growth of diffuse largeB-cell lymphoma TMD8 cells as shown by reduced number of viable cellsfollowing treatment with Example 80.

FIG. 2—Compounds of this disclosure inhibit the growth of neuroblastomaNB-1 cells as shown by reduced number of viable cells followingtreatment with Example 80.

FIG. 3—Compounds of this disclosure inhibit the growth of glioblastomaGli56 cells as shown by reduced number of viable cells followingtreatment with Example 80.

FIG. 4—Compounds of this disclosure inhibit the growth of glioblastomaD423 cells as shown by reduced number of viable cells followingtreatment with Example 80.

FIG. 5—Compounds of this disclosure inhibit the growth of NB-1xenografts in vivo, daily oral treatment with 10 mg/kg of Example 80reduces the tumor growth.

FIG. 6—Compounds of this disclosure inhibit the growth of leukemiaOCI-AML3 cells as shown by reduced number of viable cells followingtreatment with Example 80.

FIG. 7—Compounds of this disclosure reduce disease burden in humanleukemia model, daily oral treatment with 10 mg/kg of Example 80 reducesdisease burden in OCI-AML3 models in NSG mice as measured by IVISimaging.

FIG. 8—Compounds of this disclosure prolong the survival in humanleukemia model, daily oral treatment with 10 mg/kg of Example 80 extendssurvival in OCI-AML3 models in NSG mice.

FIG. 9—Mesylate, besylate, and hydrochloride salts of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleshow improved oral bioavailability in comparison to the free base.

FIG. 10—XRPD overlay of the solids obtained from salt preparations.

FIG. 11—DSC of the hydrochloride salt of Example 80.

FIG. 12—The hydrochloride salt of Example 80 after DVS.

FIG. 13—DSC of the mesylate salt of Example 80.

FIG. 14—The mesylate salt of Example 80 after DVS.

FIG. 15—TGA-MS of hydrochloride salt of Example 80.

FIG. 16—TGA-MS of mesylate salt of Example 80

DEFINITIONS

To facilitate understanding of the disclosure, a number of terms andabbreviations as used herein are defined below as follows:

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. When a conflict occurs, themeaning ascribed herein controls.

When ranges of values are disclosed, and the notation “from n1 . . . ton2” is used, where n1 and n2 are the numbers, then unless otherwisespecified, this notation is intended to include the numbers themselvesand the range between them. This range may be integral or continuousbetween and including the end values. By way of example, the range “from2 to 6 carbons” is intended to include two, three, four, five, and sixcarbons, since carbons come in integer units. Compare, by way ofexample, the range “from 1 to 3 μM (micromolar),” which is intended toinclude 1 μM, 3 μM, and everything in between to any number ofsignificant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—), (—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)N(R′)—group, withR and R′ as defined herein or as defined by the specifically enumerated“R” groups designated. The term “acylamino” as used herein, alone or incombination, embraces an acyl group attached to the parent moietythrough an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl, any of which may themselves beoptionally substituted. Additionally, R and R′ may combine to formheterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group, with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type, including spiro-ring fusedsystems. The bicyclic and tricyclic types of isomer are exemplified ingeneral by, bicyclo[1,1,1]pentane, camphor, adamantane,bicyclo[3,2,1]octane, and [4,4,1]-bicyclononane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from O, N, or S, and whereinthe nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N and S may be placed at any interior position of the heteroalkyl group.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom O, S, or N. In certain embodiments, said heteroaryl will comprisefrom 5 to 7 carbon atoms. The term also embraces fused polycyclic groupswherein heterocyclic rings are fused with aryl rings, wherein heteroarylrings are fused with other heteroaryl rings, wherein heteroaryl ringsare fused with heterocycloalkyl rings, or wherein heteroaryl rings arefused with cycloalkyl rings. Examples of heteroaryl groups includepyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl,benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl,benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl,tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl,pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groupsinclude carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl,acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each said heteroatom may be independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, saidheterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members.In further embodiments, said heterocycloalkyl will comprise from 1 to 2heteroatoms as ring members. In certain embodiments, saidheterocycloalkyl will comprise from 3 to 8 ring members in each ring. Infurther embodiments, said heterocycloalkyl will comprise from 3 to 7ring members in each ring. In yet further embodiments, saidheterocycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,cyclic sulfonamides, sulfoxides, N-oxides of tertiary nitrogen ringmembers, and carbocyclic fused, benzo fused, and spiro-ring fused ringsystems; additionally, both terms also include systems where aheterocycle ring is fused to an aryl group, as defined herein, or anadditional heterocycle group. Examples of heterocycle groups includeaziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl,dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, isothiazolidine, andthe like. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrogen,” as used herein, refers to both protium (¹H) anddeuterium (²H). This definition extends to hydrogen atoms which appearin chemical structural drawings disclosed herein, including at siteswhere hydrogen atoms are not explicitly shown. For example, a chemicalstructure disclosed herein may include an ethyl group represented as

which includes five hydrogen atoms which are not explicitly drawn, anyof which can be protium (¹H) or deuterium (²H). This definition alsoextends to hydrogen atoms which form a part of a named chemicalsubstituent disclosed herein. For example, a generic chemical structuredisclosed herein may recite an aryl group, which encompasses specificembodiments such as a phenyl group, which comprises five hydrogen atoms,any of which can be protium (¹H) or deuterium (²H).

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156%, deuterium enrichment at any position in acompound synthesized using non-enriched starting materials is about0.0156%. The deuterium enrichment can be determined using conventionalanalytical methods known to one of ordinary skill in the art, includingmass spectrometry and nuclear magnetic resonance spectroscopy.

In certain embodiments, compounds disclosed herein are enriched withdeuterium. Carbon-hydrogen bond strength is directly proportional to theabsolute value of the ground-state vibrational energy of the bond. Thisvibrational energy depends on the mass of the atoms that form the bond,and increases as the mass of one or both of the atoms making the bondincreases. Since deuterium (D) has twice the mass of protium (¹H), a C-Dbond is stronger than the corresponding C—¹H bond. If a C—¹H bond isbroken during a rate-determining step in a chemical reaction (i.e. thestep with the highest transition state energy), then substituting adeuterium for that protium will cause a decrease in the reaction rate,including cases where a C—H bond is broken during metabolism of acompound disclosed herein. This phenomenon is known as the DeuteriumKinetic Isotope Effect (DKIE). The magnitude of the DKIE can beexpressed as the ratio between the rates of a given reaction in which aC—¹H bond is broken, and the same reaction where deuterium issubstituted for protium. The DKIE can range from about 1 (no isotopeeffect) to very large numbers, such as 50 or more. The deuterationapproach has the potential to slow the metabolism of the compoundsdisclosed herein. Various deuteration patterns can be used to (a) reduceor eliminate unwanted metabolites, (b) increase the half-life of theparent drug, (c) decrease the number of doses needed to achieve adesired effect, (d) decrease the amount of a dose needed to achieve adesired effect, (e) increase the formation of active metabolites, if anyare formed, (f) decrease the production of deleterious metabolites inspecific tissues, and/or (g) create a more effective drug and/or a saferdrug for polypharmacy, whether the polypharmacy be intentional or not.Deuterium can be introduced into a compound as disclosed herein bysynthetic techniques that employ deuterated reagents, wherebyincorporation rates are predetermined; and/or by exchange techniques,wherein incorporation rates are determined by equilibrium conditions,and may be highly variable depending on the reaction conditions.Synthetic techniques where deuterium is directly and specificallyinserted by a deuterated reagent of known isotopic content, can yieldhigh deuterium abundance, but can be limited by the chemistry required.Exchange techniques, on the other hand, may yield lower deuteriumincorporation, often with the isotope being distributed over many siteson the molecule.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomsselected from O, S, or N, or 2) bicyclic heteroaryl, wherein each of thefused rings comprises five or six ring members, comprising between themone to four heteroatoms selected from the group consisting of O, S, andN.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomsselected from the group consisting of O, S, and N. Examples of lowerheterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls maybe unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, lower alkyl, and lower heteroalkyl, any of whichmay be optionally substituted. Additionally, the R and R′ of a loweramino group may combine to form a five- or six-memberedheterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer to the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any chemical definition herein may be used in combination with any otherchemical definition to describe a composite structural group. Byconvention, the trailing element of any such definition is that whichattaches to the parent moiety. For example, the composite groupalkylamido would represent an alkyl group attached to the parentmolecule through an amido group, and the term alkoxyalkyl wouldrepresent an alkoxy group attached to the parent molecule through analkyl group.

A “salt” as used herein means an ionic compound with a net neutralcharge formed by combination of one type of a cation with one type of ananion in an integer or non-integer ratio, and optionally with one typeof associated solvent molecule in an integer or non-integer ratio. Theterm “compound as disclosed herein” or “compound of this disclosure”includes salts.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, any of which may be optionallysubstituted. Such R and R′ groups should be understood to be optionallysubstituted as defined herein. Whether an R group has a numberdesignation or not, every R group, including R, R′ and R^(n) where n=(1,2, 3, . . . n), every substituent, and every term should be understoodto be independent of every other in terms of selection from a group.Should any variable, substituent, or term (e.g. aryl, heterocycle, R,etc.) occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the disclosure encompasses all stereochemicalisomeric forms, including diastereomeric, enantiomeric, and epimericforms, as well as d-isomers and 1-isomers, and mixtures thereof.Individual stereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentdisclosure includes all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.Additionally, compounds may exist as tautomers; all tautomeric isomersare provided by this disclosure. Additionally, the compounds disclosedherein can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. In general, the solvated forms are considered equivalent to theunsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position. When a group in a chemical formula is designated to be “abond,” the group reduces to a linkage between the groups to which it islinked in the formula. By way of example, in Formula I, when Y₂ is abond, it becomes a direct link between A and -alkyl-N(R₄)R₅, formingR₅(R₄)N-alkyl-A-Y₁—(B—(R₂)_(m))—D-E-(R₃)_(p).

As used herein, the term “modulate” means to increase or decrease theactivity of a target or the amount of a substance.

As used herein, the term “increase” or the related terms “increased,”“enhance” or “enhanced” refers to a statistically significant increase,and the terms “decreased,” “suppressed,” or “inhibited” to astatistically significant decrease. For the avoidance of doubt, anincrease generally refers to at least a 10% increase in a givenparameter, and can encompass at least a 20% increase, 30% increase, 40%increase, 50% increase, 60% increase, 70% increase, 80% increase, 90%increase, 95% increase, 97% increase, 99% or even a 100% increase overthe control, baseline, or prior-in-time value. Inhibition generallyrefers to at least a 10% decrease in a given parameter, and canencompass at least a 20% decrease, 30% decrease, 40% decrease, 50%decrease, 60% decrease, 70% decrease, 80% decrease, 90% decrease, 95%decrease, 97% decrease, 99% or even a 100% decrease over the controlvalue.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the human or animal body or of one of its parts thatimpairs normal functioning, is typically manifested by distinguishingsigns and symptoms, and causes the human or animal to have a reducedduration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single formulation (e.g., a capsule orinjection) having a fixed ratio of active ingredients or in multiple,separate dosage forms for each active ingredient. In addition, suchadministration also encompasses use of each type of therapeutic agent ina sequential manner. In either case, the treatment regimen will providebeneficial effects of the drug combination in treating the conditions ordisorders described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the saiddisease or disorder.

The term “therapeutically acceptable” refers to those compounds (orsalts, polymorphs, prodrugs, tautomers, zwitterionic forms, etc.) whichare suitable for use in contact with the tissues of patients withoutundue toxicity, irritation, and allergic response, are commensurate witha reasonable benefit/risk ratio, and are effective for their intendeduse.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis.

In the present disclosure, the term “radiation” means ionizing radiationcomprising particles or photons that have sufficient energy or canproduce sufficient energy via nuclear interactions to produce ionization(gain or loss of electrons). An exemplary and preferred ionizingradiation is an x-radiation. Means for delivering x-radiation to atarget tissue or cell are well known in the art. The amount of ionizingradiation needed in a given cell generally depends on the nature of thatcell. Means for determining an effective amount of radiation are wellknown in the art. Used herein, the term “an effective dose” of ionizingradiation means a dose of ionizing radiation that produces an increasein cell damage or death.

The term “radiation therapy” refers to the use of electromagnetic orparticulate radiation in the treatment of neoplasia and includes the useof ionizing and non-ionizing radiation.

As used herein, the term “patient” means all mammals including humans.Examples of patients include humans, cows, dogs, cats, goats, sheep,pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound and N-oxides of amines or heterocyclic groups such as pyridine.

The term “metabolite” refers to a compound produced through biologicaltransformation of a compound following administration to a subject. Inorder to eliminate foreign substances such as therapeutic agents, theanimal body expresses various enzymes, such as the cytochrome P450enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, andmonoamine oxidases, to react with and convert these foreign substancesto more polar intermediates or metabolites for renal excretion. Suchmetabolic reactions frequently involve the oxidation of acarbon-hydrogen (C—H) bond to either a carbon-oxygen (C—O) or acarbon-carbon (C—C)-bond, N-oxidation, or covalent bonding of a polarmolecule or functional group (such as sulfate, glucuronic acid,glutathione, or glycine, to the therapeutic agent. The resultantmetabolites may be stable or unstable under physiological conditions,and can have substantially different pharmacokinetic, pharmacodynamic,and acute and long-term toxicity profiles relative to the parentcompounds. Certain compounds disclosed herein may, after administrationto a subject result in formation of metabolites, which in some caseshave biological activity as HIF pathway modulators or activity againstother biological systems. In certain embodiments, metabolites of thecompounds disclosed herein include N-oxides, particularly N-oxides ofheterocyclic groups such as pyridine. In further embodiments,metabolites of compounds disclosed herein may themselves havesubstantial activity as HIF pathway inhibitors.

The compounds disclosed herein can exist as therapeutically acceptablesalts. Suitable acid addition salts include those formed with bothorganic and inorganic acids, and will normally be pharmaceuticallyacceptable. However, salts of non-pharmaceutically acceptable salts maybe of utility in the preparation and purification of the compound inquestion. Basic addition salts may also be formed and bepharmaceutically acceptable. Representative acid addition salts includeacetate, adipate, alginate, L-ascorbate, aspartate, benzoate,benzenesulfonate (besylate), bisulfate, butyrate, camphorate,camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate,glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate,DL-mandelate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate,picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate,tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate,glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), andundecanoate. Also, basic groups in the compounds disclosed herein can bequaternized with methyl, ethyl, propyl, and butyl chlorides, bromides,and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl,lauryl, myristyl, and steryl chlorides, bromides, and iodides; andbenzyl and phenethyl bromides. For a more complete discussion of thepreparation and selection of salts, refer to Pharmaceutical Salts:Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich,Switzerland, Second, Revised Edition, 2011.2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid. Examples ofacids which can be employed to form therapeutically acceptable additionsalts include inorganic acids such as hydrochloric, hydrobromic,sulfuric, and phosphoric, and organic acids such as oxalic, maleic,succinic, and citric. Salts can also be formed by coordination of thecompounds with an alkali metal or alkaline earth ion.

Basic addition salts can be prepared during the final isolation andpurification of the compounds, often by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium (e.g., NaOH), potassium (e.g., KOH), calcium (includingCa(OH)₂), magnesium (including Mg(OH)₂ and magnesium acetate), zinc,(including Zn(OH)₂ and zinc acetate) and aluminum, as well as nontoxicquaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine,choline hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrrolidone,imidazole, n-methyl-d-glucamine, N, N′-dibenzylethylenediamine, N,N′-diethylethanolamine, N, N′-dimethylethanolamine, triethanolamine, andtromethamine. Basic amino acids such as 1-glycine and 1-arginine, andamino acids which may be zwitterionic at neutral pH, such as betaine(N,N,N-trimethylglycine) are also contemplated.

Salts disclosed herein may combine in 1:1 molar ratios, and in fact thisis often how they are initially synthesized. However, it will berecognized by one of skill in the art that the stoichiometry of one ionin a salt to the other may be otherwise. Salts shown herein may be, forthe sake of convenience in notation, shown in a 1:1 ratio; all possiblestoichiometric arrangements are encompassed by the scope of the presentdisclosure.

The terms, “polymorphs” and “polymorphic forms” and related terms hereinrefer to crystal forms of the same molecule, and different polymorphsmay have different physical properties such as, for example, meltingtemperatures, heats of fusion, solubilities, dissolution rates and/orvibrational spectra as a result of the arrangement or conformation ofthe molecules in the crystal lattice. The differences in physicalproperties exhibited by polymorphs affect pharmaceutical parameters suchas storage stability, compressibility and density (important informulation and product manufacturing), and dissolution rates (animportant factor in bioavailability). Differences in stability canresult from changes in chemical reactivity (e.g. differential oxidation,such that a dosage form discolors more rapidly when comprised of onepolymorph than when comprised of another polymorph) or mechanicalchanges (e.g. tablets crumble on storage as a kinetically favoredpolymorph converts to thermodynamically more stable polymorph) or both(e.g., tablets of one polymorph are more susceptible to breakdown athigh humidity). As a result of solubility/dissolution differences, inthe extreme case, some polymorphic transitions may result in lack ofpotency or, at the other extreme, toxicity. In addition, the physicalproperties of the crystal may be important in processing, for example,one polymorph might be more likely to form solvates or might bedifficult to filter and wash free of impurities (i.e., particle shapeand size distribution might be different between polymorphs).

Polymorphs of a molecule can be obtained by a number of methods, asknown in the art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization, desolvation,rapid evaporation, rapid cooling, slow cooling, vapor diffusion andsublimation.

The term, “solvate,” as used herein, refers to a crystal form of asubstance which contains solvent. The term “hydrate” refers to a solvatewherein the solvent is water.

Techniques for characterizing polymorphs include, but are not limitedto, differential scanning calorimetry (DSC), X-ray powder diffractometry(XRPD), thermal gravimetric analysis (TGA), dynamic vaporsorption/desorption (DVS), single crystal X-ray diffractometry,vibrational spectroscopy, e.g. IR and Raman spectroscopy, solid stateNMR, hot stage optical microscopy, scanning electron microscopy (SEM),electron crystallography and quantitative analysis, particle sizeanalysis (PSA), surface area analysis, solubility studies anddissolution studies.

As used herein, “solid” when referring to a salt form means relativelysolid, at room temperature, and/or containing a substantial amount ofsolids. A solid may be amorphous in form and/or be a solvated solid withsome quantity of residual or coordinated of solvent molecules. Acrystalline salt is an example of a solid. By way of example, a waxcould be considered a solid, whereas an oil would not be.

A “solid composition” as used herein includes a salt of a compound, or apolymorph or amorphous solid form thereof.

While it may be possible for the compounds and prodrugs disclosed hereinto be administered as the raw chemical, it is also possible to presentthem as a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds and prodrugs disclosed herein, or one or more pharmaceuticallyacceptable salts, esters, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal,intranasal, rectal and topical (including dermal, buccal, sublingual andintraocular) administration although the most suitable route may dependupon for example the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy.Typically, these methods include the step of bringing into association acompound of the subject disclosure or a pharmaceutically acceptablesalt, ester, amide, prodrug or solvate thereof (“active ingredient”)with the carrier which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired formulation.

Formulations of the compounds and prodrugs disclosed herein suitable fororal administration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds and prodrugs may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycols. In addition, stabilizers maybe added. Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

The compounds and prodrugs may be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundsand prodrugs which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds and prodrugs to allow for the preparation of highlyconcentrated solutions.

In addition to the formulations described previously, a compound orprodrug as disclosed herein may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds and prodrugsmay be formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds and prodrugs may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds and prodrugs disclosed herein may be administeredtopically, that is by non-systemic administration. This includes theapplication of a compound disclosed herein externally to the epidermisor the buccal cavity and the instillation of such a compound into theear, eye and nose, such that the compound does not significantly enterthe blood stream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

For administration by inhalation, compounds and prodrugs may beconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, the compounds and prodrugsdisclosed herein may take the form of a dry powder composition, forexample a powder mix of the compound and a suitable powder base such aslactose or starch. The powder composition may be presented in unitdosage form, in for example, capsules, cartridges, gelatin or blisterpacks from which the powder may be administered with the aid of aninhalator or insufflator.

Intranasal delivery, in particular, may be useful for deliveringcompounds to the CNS. It had been shown that intranasal drugadministration is a noninvasive method of bypassing the blood-brainbarrier (BBB) to deliver neurotrophins and other therapeutic agents tothe brain and spinal cord. Delivery from the nose to the CNS occurswithin minutes along both the olfactory and trigeminal neural pathways.Intranasal delivery occurs by an extracellular route and does notrequire that drugs bind to any receptor or undergo axonal transport.Intranasal delivery also targets the nasal associated lymphatic tissues(NALT) and deep cervical lymph nodes. In addition, intranasallyadministered therapeutics are observed at high levels in the bloodvessel walls and perivascular spaces of the cerebrovasculature. Usingthis intranasal method in animal models, researchers have successfullyreduced stroke damage, reversed Alzheimer's neurodegeneration, reducedanxiety, improved memory, stimulated cerebral neurogenesis, and treatedbrain tumors. In humans, intranasal insulin has been shown to improvememory in normal adults and patients with Alzheimer's disease. Hanson LR and Frey W H, 2nd, J Neuroimmune Pharmacol. 2007 March; 2(1):81-6.Epub 2006 Sep. 15.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds and prodrugs may be administered orally or via injection at adose of from 0.1 to 500 mg/kg per day. The dose range for adult humansis generally from 5 mg to 2 g/day. Tablets or other forms ofpresentation provided in discrete units may conveniently contain anamount of one or more compound or prodrug which is effective at suchdosage or as a multiple of the same, for instance, units containing 5 mgto 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds and prodrugs can be administered in various modes, e.g.orally, topically, or by injection. The precise amount of compoundadministered to a patient will be the responsibility of the attendantphysician. The specific dose level for any particular patient willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general health, sex, diets,time of administration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds and prodrugs described herein (or a pharmaceuticallyacceptable salt or ester thereof) in combination with anothertherapeutic agent. By way of example only, if one of the side effectsexperienced by a patient upon receiving one of the compounds herein forthe treatment of cancer is nausea, then it may be appropriate toadminister an antiemetic agent in combination. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for cancer involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for cancer. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

The compounds disclosed herein, including compounds of Formula I, arealso useful as chemo- and radio-sensitizers for cancer treatment. Theyare useful for the treatment of mammals which have previously undergoneor are presently undergoing or will be undergoing treatment for cancer.Such other treatments include chemotherapy, radiation therapy, surgeryor immunotherapy, such as cancer vaccines.

The instant compounds are particularly useful in combination withtherapeutic, anti-cancer and/or radiotherapeutic agents. Thus, thepresent disclosure provides a combination of the presently compounds ofFormula I with therapeutic, anti-cancer and/or radiotherapeutic agentsfor simultaneous, separate or sequential administration. The compoundsof this disclosure and the other anticancer agent can act additively orsynergistically. A synergistic combination of the present compounds andanother anticancer agent might allow the use of lower dosages of one orboth of these agents and/or less frequent dosages of one or both of theinstant compounds and other anticancer agents and/or to administer theagents less frequently can reduce any toxicity associated with theadministration of the agents to a subject without reducing the efficacyof the agents in the treatment of cancer. In addition, a synergisticeffect might result in the improved efficacy of these agents in thetreatment of cancer and/or the reduction of any adverse or unwanted sideeffects associated with the use of either agent alone.

The therapeutic agent, anti-cancer agent and/or radiation therapy can beadministered according to therapeutic protocols well known in the art.It will be apparent to those skilled in the art that the administrationof the therapeutic agent, anti-cancer agent and/or radiation therapy canbe varied depending on the disease being treated and the known effectsof the anti-cancer agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., anti-neoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents, and observed adverse affects.

Dosage ranges for x-rays range from daily doses of 50 to 200 roentgensfor prolonged periods of time (3 to 4 weeks), to single doses of 2000 to6000 roentgens. Dosage ranges for radioisotopes vary widely, and dependon the half-life of the isotope, the strength and type of radiationemitted, and the uptake by the neoplastic cells.

Any suitable means for delivering radiation to a tissue may be employedin the present disclosure. Common means of delivering radiation to atissue is by an ionizing radiation source external to the body beingtreated. Alternative methods for delivering radiation to a tissueinclude, for example, first delivering in vivo a radiolabeled antibodythat immunoreacts with an antigen of the tumor, followed by deliveringin vivo an effective amount of the radio labeled antibody to the tumor.In addition, radioisotopes may be used to deliver ionizing radiation toa tissue or cell. Additionally, the radiation may be delivered by meansof a radiomimetic agent. As used herein a “radiomimetic agent” is achemotherapeutic agent, for example melphalan, that causes the same typeof cellular damage as radiation therapy, but without the application ofradiation.

In one embodiment, the compounds of formula I can be administered incombination with one or more agent selected from aromatase inhibitors,anti-estrogens, anti-progesterons, anti-androgens, or gonadorelinagonists, anti-inflammatory agents, antihistamines, anti-cancer agent,inhibitors of angiogenesis, topoisomerase 1 and 2 inhibitors,microtubule active agents, alkylating agents, antineoplastic,antimetabolite, dacarbazine (DTIC), platinum containing compound, lipidor protein kinase targeting agents, protein or lipid phosphatasetargeting agents, anti-angiogenic agents, agents that induce celldifferentiation, bradykinin 1 receptor and angiotensin II antagonists,cyclooxygenase inhibitors, heparanase inhibitors, lymphokines orcytokine inhibitors, bisphosphonates, rapamycin derivatives,anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPARagonists, HSP90 inhibitor, smoothened antagonist, inhibitors of Rasisoforms, telomerase inhibitors, protease inhibitors, metalloproteinaseinhibitors, aminopeptidase inhibitors, imununomodulators, therapeuticantibody and a protein kinase inhibitor, e.g., a tyrosine kinase orserine/threonine kinase inhibitor.

In another embodiment is provided a combination of a compound of formulaI and an anti-cancer agent for simultaneous, separate or sequentialadministration.

Examples of cancer agents or chemotherapeutic agents for use incombination with the compounds as disclosed herein can be found inCancer Principles and Practice of Oncology by V. T. Devita and S.Hellman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers, and WO 2006/061638. A person of ordinary skill inthe art would be able to discern which combinations of agents would beuseful based on the particular characteristics of the drugs and thecancer involved. Classes of such agents include the following: estrogenreceptor modulators, androgen receptor modulators, retinoid receptormodulators, cytotoxic/cytostatic agents, antiproliferative agents,prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors andother angiogenesis inhibitors, HIV protease inhibitors, reversetranscriptase inhibitors, inhibitors of cell proliferation and survivalsignaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics,γ-secretase inhibitors, agents that interfere with receptor tyrosinekinases (RTKs), agents that interfere with cell cycle checkpoints, PARPinhibitors, HDAC inhibitors, Smo antagonists (HH inhibitors), HSP90inhibitors, CYP17 inhibitors, 3rd generation AR antagonists, JAKinhibitors e.g. Ruxolitinib (trade name Jakafi, and BTK kinaseinhibitors.

Anticancer agents suitable for use in the combination therapy withcompounds as disclosed herein include, but are not limited to: 1)alkaloids and natural product drugs, including, microtubule inhibitors(e.g., Vincristine, Vinblastine, and Vindesine, and vinorelbine etc.),microtubule stabilizers (e.g., Paclitaxel [Taxol], and Docetaxel,Taxotere, etc.), and chromatin function inhibitors, including,topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide[VP-161, and Teniposide [VM-261, etc.), and agents that targettopoisomerase I (e.g., Camptothecin, topotecan (Hycamtin) and Irinotecan[CPT-11], rubitecan (Orathecin)etc.); 2) covalent DNA-binding agents[alkylating agents], including, nitrogen mustards (e.g.,Mechloretharnine, chlormethine, Chlorambucil, Cyclophosphamide,estramustine (Emcyt, Estracit), ifosfamide, Ifosphamide, melphalan(Alkeran) etc.); alkyl sulfonates like Busulfan [Myleran], nitrosoureas(e.g., Carmustine or BCNU (bis-chloroethylnitrosourea), fotemustineLomustine, and Semustine, streptozocin etc.), and other alkylatingagents (e.g., Dacarbazine, procarbazine ethylenimine/methylmelamine,thriethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa),hexamethylmelamine (HMM, altretamine), and Mitocycin, uramustine etc.)including Temozolomide (brand names Temodar and Temodal and Temcad),altretamine (also hexalen) and mitomycin; 3) noncovalent DNA-bindingagents [antitumor antibiotics], including nucleic acid inhibitors (e.g.,Dactinomycin [Actinomycin D1, etc.), anthracyclines (e.g., Daunorubicin[Daunomycin, and Cerubidine], Doxorubicin [Adrianycin], epirubicin(Ellence), and Idarubicin [Idamycin], valrubicin (Valstar) etc.),anthracenediones (e.g., anthracycline analogues, such as,[Mitoxantrone], etc.), bleomycins (Blenoxane), etc., amsacrine andplicamycin (Mithramycin), dactinomycin, mitomycin C: 4) antimetabolites,including, antifolates (e.g., Methotrexate, Folex, aminopterin,pemetrexed, raltitrexed and Mexate, trimetrexate etc.), purineantimetabolites (e.g., 6-Mercaptopurine[6-MP, Purinethol], cladribine,6-Thioguanine[6-TG], clofarabine (Clolar, Evoltra), Azathioprine,Acyclovir, Fludarabine or fludarabine phosphate (Fludara) Ganciclovir,Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine [CdA], and2′-Deoxycoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g.,fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine(FdUrd) (Floxuridine)], capecitabine Carmofur or HCFU(1-hexylcarbamoyl-5-fluorouracil), tegafur etc.), gemcitabine (Gemzar),and cytosine arabinosides (e.g., Cytarabine, or cytosine arabinoside,Cytosar [ara-C] and Fludarabine, 5-azacytidine,2,2′-difluorodeoxycytidine etc.) and hydroxyurea (Hydrea and Droxia,hydroxycarbamide), plus lonidamine; 5) enzymes, including,L-asparaginase and derivatives such as pegaspargase (Oncaspar), andRNAse A; 7) hormones and antagonists, Examples of hormones and hormonalanalogues believed to be useful in the treatment of neoplasms include,but are not limited to antiestrogens and selective estrogen receptormodulators (SERMs), such as tamoxifen, toremifene, raloxifene,iodoxyfene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene,onapristone; anti-androgens; such as enzalutamide (Xtandi®), flutamide,nilutamide, bicalutamide, leuprolide, and goserelin, and cyproteroneacetate; adrenocorticosteroids such as prednisone and prednisolone;aminoglutethimide, finasteride and other aromatase inhibitors such asanastrozole, letrazole, vorazole, exemestane, formestanie, andfadrozole; Estrogen Receptor Downregulators (EROs) including Faslodex orfulvestrant, progestrins such as megestrol acetate; Sa-reductaseinhibitors such as finasteride and dutasteride; andgonadotropin-releasing hormones (GnRH) and analogues thereof, such asLeutinizing Hormone-releasing Hormone (LHRH) agonists and antagonistssuch as goserelin luprolide, leuprorelin and buserelin; 8) platinumcompounds (e.g., Cisplatin and Carboplatin, oxaliplatin, Triplatintetranitrate (rINN; also known as BBR3464), eptaplatin, lobaplatin,nedaplatin, or satraplatin etc.); 9) retinoids such as bexarotene(Targretin); 10) proteasome inhibitors such as bortezomib andcarfilzomib (Kyprolis®); 11) anti-mitotics in addition to diterpenoidsand vinca alkaloids include polo-like kinase (PLK) inhibitors, mitotickinesin spindle protein (KSP) inhibitors including SB-743921 and MK-833and CenpE inhibitors; 12) monoclonal antibodies, including cancerimmunotherapy monoclonal antibodies and humanized monoclonal antibodies.For example: 12-a) cancer immunotherapy monoclonal antibodies includeagents selected from the group consisting of Trastuzumab (Herceptin®),an example of an anti-erbB2 antibody inhibitor of growth factorfunction; cetuximab (Erbitux™ C225), an example of an anti-erbB1antibody inhibitor of growth factor function; bevacizumab (Avastin®), anexample of a monoclonal antibody directed against VEGFR; rituximab,alemtuzumab, gemtuzumab, panitumumab, tositumomab, pertuzumab; 12-b)humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination include: alemtuzumab, apolizumab,aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumabmertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol,cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab,epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin,inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab,mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab,nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab,pascolizumab, pecfusituzumab, pectuzumab, pertuzumab (Perjeta®),pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab,resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab,sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab,tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin,tucusituzumab, umavizumab, urtoxazumab, and visilizumab; 13) monoclonalantibodies conjugated with anticancer drugs, toxins, and/orradionuclides, etc. gemtuzumab ozogamicin (MYLOTARG), trastuzumabemtansine (T-DM1)/ado-trastuzumab emtansine (Kadcyla®); 14) biologicalresponse modifiers (e.g., interferons [e.g., IFN-.alpha., etc.] andinterleukins [e.g., IL-2, etc.], denileukin diftitox (Ontak), G-CSF,GM-CSF: etc.); 15) adoptive immunotherapy; Immunotherapeutic regimensinclude ex-vivo and in-vivo approaches to increasing immunogenicity ofpatient tumor cells such as transfection with cytokines (eg. IL-2 oraldesleukin, IL-4, GMCFS), as well as IL-1, IL-3, IL-4, IL-5, IL-6,IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, and active biological variantsapproaches to increase T-cell activity, approaches with transfectedimmune cells and approaches with antiidiotypic antibodies; 16)immunosuppressant selected from the group consisting of fingolimod,cyclosporine A, Azathioprine, dexamethasone, tacrolimus, sirolimus,pimecrolimus, mycophenolate salts, everolimus, basiliximab, daclizumab,anti-thymocyte globulin, anti-lymphocyte globulin, and tofacitinib.Agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocyte antigen 4) antibodies such as Ipilimumab (MDX-010or MDX-101, Yervoy) and tremelimumab, and other agents capable ofblocking CTLA4; 17) immune modulators, for use in conjunction with thecompound as disclosed herein include staurosprine and macrocyclicanalogs thereof, including UCN-01, CEP-701 and midostaurin; squalamine;DA-9601; alemtuzumab; interferons (e.g. IFN-α, IFN-b etc.); altretamine(Hexalen®); SU 101 or leflunomide; imidazoquinolines such as resiquimod,imiquimod, anti-PD-1 human monoclonal antibodies MDX-1106 (also known asBMS-936558), MK3475, CT-011, and AMP-224, anti-PD-L1 monoclonalantibodies such as MDX-1105, anti-OX40 monoclonal antibodies, and LAG3fusion proteins such as IMP321g, anti-B7-H3 monoclonal antibodies suchas MGA271, anti-B7-H4 monoclonal antibodies, and anti-TIM3 monoclonalantibodies; 18) hematopoietic growth factors; 19) agents that inducetumor cell differentiation (e.g., tretinoin (all trans retinoic acid)(brand names Aberela, Airol, Renova, Atralin, Retin-A, Avita, Retacnyl,Refissa, or Stieva-A)); 20) gene therapy techniques; such as genetherapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and V AXID®; 21)antisense therapy techniques; 22) tumor vaccines; include Avicine®;oregovomab (OvaRex®); Theratope® (STn-KLH); Melanoma Vaccines; GI-4000series (GI-4014, GI-4015, and GI-4016), which are directed to fivemutations in the Ras protein; GlioVax-1; MelaVax; Advexin® or INGN-201;Sig/E7/LAMP-1, encoding HPV-16 E7; MAGE-3 Vaccine or M3TK; HER-2VAX;ACTIVE, which stimulates T-cells specific for tumors; GM-CSF cancervaccine; and Listeria onocytogenes-based vaccines; 23) therapiesdirected against tumor metastases (e.g., Batimistat, etc.); 24)inhibitors of angiogenesis. Receptor kinase angiogenesis inhibitors mayalso find use in the present disclosure. Inhibitors of angiogenesisrelated to VEGFR and TIE-2. Other inhibitors may be used in combinationwith the compounds of the disclosure. For example, anti-VEGF antibodies,which do not recognize VEGFR (the receptor tyrosine kinase), but bind tothe ligand; small molecule inhibitors of integrin (alphav beta3) thatinhibit angiogenesis; endostatin and angiostatin (non-RT) may also proveuseful in combination with the compounds of the disclosure. One exampleof a VEGFR antibody is bevacizumab (Avastin®). Other anti-angiogeniccompounds include acitretin, fenretinide, thalidomide, zoledronic acid,angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin,halofuginone, rebimastat, removab, Lenalidomid (Revlimid), squalamine,Vitaxin, and pomalidomide (Pomalyst®); 25) signal transduction pathwayinhibitors. Signal transduction pathway inhibitors are those inhibitorswhich block or inhibit a chemical process which evokes an intracellularchange. As used herein these changes include, but are not limited to,cell proliferation or differentiation or survival. Signal transductionpathway inhibitors useful in the present disclosure include, but are notlimited to, inhibitors of receptor tyrosine kinases, non-receptortyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases,phosphatidyl inositoi-3-0H kinases, myoinositol signaling, and Rasoncogenes. Signal transduction pathway inhibitors may be employed incombination with the compounds of the disclosure; 26) kinase inhibitors,including tyrosine kinases, serine/threonine kinases, kinases involvedin the IGF-1 R signaling axis, PI3k/AKT/mTOR pathway inhibitors, andSH2/SH3 domain blockers. Examples of relevant kinases include: 26-a)tyrosine kinases. Several protein tyrosine kinases catalyze thephosphorylation of specific tyrosine residues in various proteinsinvolved in the regulation of cell growth. Such protein tyrosine kinasescan be broadly classified as receptor or non-receptor kinases. Receptortyrosine kinase inhibitors which may be combined with the compounds ofthe disclosure include those involved in the regulation of cell growth,which receptor tyrosine kinases are sometimes referred to as “growthfactor receptors.” Examples of growth factor receptor inhibitors,include but are not limited to inhibitors of: insulin growth factorreceptors (IGF-1 R, IR and IRR); epidermal growth factor familyreceptors (EGFR, ErbB2, and ErbB4); platelet derived growth factorreceptors (PDGFRs), vascular endothelial growth factor receptors(VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growthfactor homology domains (TIE-2), macrophage colony stimulating factor(c-FMS), c-KIT, cMET, fibroblast growth factor receptors (FGFRs),hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB,and TrkC), ephrin (Eph) receptors, the RET protooncogene, and HumanEpidermal Growth Factor Receptor 2 (HER-2). Examples of small moleculeinhibitors of epidermal growth factor receptors include but are notlimited to gefitinib, lapatinib (Tykerb®), erlotinib (Tarceva®),afatinib (Gilotrif®, Tomtovok®, and Tovok®), and. lmatinib (Gleevec®) isone example of a PDGFR inhibitor. Examples of VEGFR inhibitors includepazopanib (Votrient™) Vandetanib (ZD6474), AZD2171, vatalanib (PTK-787),Axitinib (AG013736; Inlyta®), dovitinib (CHIR-258), cabozantinib(Cometriq®), sunitinib, and sorafenib. Protein Kinase C (PKC)inhibitors, such as ruboxistaurin, AEB071 (Sotrastaurin) LY-317615 andperifosine. Examples of small molecule inhibitors of multiple tyrosinekinases include but are not limited to bosutinib (Bosulif®) and. Otherkinase inhibitors include but are not limited to BIBF-1120, dasatinib(sprycel), pelitinib, nilotinib, and lestaurtinib (CEP-701). Tyrosinekinases that are not transmembrane growth factor receptor kinases aretermed non-receptor, or intracellular tyrosine kinases. Inhibitors ofnon-receptor tyrosine kinases are sometimes referred to as“anti-metastatic agents” and are useful in the present disclosure.Targets or potential targets of anti-metastatic agents, include, but arenot limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl andBcr-Abl), FAK (focal adhesion kinase) and Bruton's tyrosine kinase(BTK). Examples of small molecule inhibitors of Bcr-Abl include but arenot limited to ponatinib (Iclusig®). Non-receptor kinases and agents,which inhibit non-receptor tyrosine kinase function, are described inSinha, S. and Corey, S. J., J. Hematother. Stem Cell Res. (1999) 8465-80; and Bolen, J. B. and Brugge, J. S., Annu. Rev. of Immunol.(1997) 15 371-404; 26-b) serine/threonine kinases. Inhibitors ofserine/threonine kinases may also be used in combination with thecompounds of the disclosure in any of the compositions and methodsdescribed above. Examples of serine/threonine kinase inhibitors that mayalso be used in combination with a compound of the present disclosureinclude, but are not limited to, polo-like kinase inhibitors (Pik familye.g., Plk1, Plk2, and Plk3), which play critical roles in regulatingprocesses in the cell cycle including the entry into and the exit frommitosis; MAP kinase cascade blockers, which include other Ras/Raf kinaseinhibitors, mitogen or extracellular regulated kinases (MEKs), andextracellular regulated kinases (ERKs); Aurora kinase inhibitors(including inhibitors of Aurora A and Aurora B); protein kinase C (PKC)family member blockers, including inhibitors of PKC subtypes (alpha,beta, gamma, epsilon, mu, lambda, iota, zeta); inhibitors of kappa-B(lkB) kinase family (IKK-alpha, IKK-beta); PKB/Akt kinase familyinhibitors; and inhibitors of TGF-beta receptor kinases. Examples of Plkinhibitors are described in PCT Publication No. WO04/014899 andWO07/03036; 26-c) kinases involved in the IGF-1 R signaling axis.Inhibitors of kinases involved in the IGF-1 R signaling axis may also beuseful in combination with the compounds of the present disclosure. Suchinhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K,AKT and MEK, and 14.3.3 signaling inhibitors; 26-d) PI3k/AKT/mTORpathway inhibitors, including GDC-0941, XL-147, GSK690693 andtemsirolimus, SF-1126 (PI3K inhibitor,), BEZ-235 (PI3K inhibitor); 26-e)SH2/SH3 domain blockers. SH2/SH3 domain blockers are agents that disruptSH2 or SH3 domain binding in a variety of enzymes or adaptor proteinsincluding, but not limited to, PI3-K p85 subunit, Src family kinases,adaptor molecules (She, Crk, Nck, Grb2) and Ras-GAP. Examples of Srcinhibitors include, but are not limited to, dasatinib and BMS-354825 (J.Med. Chern. (2004) 4 7 6658-6661); 27) inhibitors of Ras oncogenes.Inhibitors of Ras oncogene may also be useful in combination with thecompounds of the present disclosure. Such inhibitors include, but arenot limited to, inhibitors of farnesyltransferase, geranyl-geranyltransferase, and CAAX proteases as well as anti-sense oligonucleotides,ribozymes and immunotherapy. Such inhibitors have been shown to blockRas activation in cells containing mutant Ras, thereby acting asantiproliferative agents; 28) Raf/MEK/ERK pathway modulators. TheRaf/MEK/ERK pathway is critical for cell survival, growth, proliferationand tumorigenesis. Li, Nanxin, et al. “B-Raf kinase inhibitors forcancer treatment.” Current Opinion in Investigational Drugs. Vol. 8, No.6 (2007): 452-456. Raf kinases exist as three isoforms, A-Raf, B-Raf andC-Raf. Among the three isoforms, studies have shown that B-Raf functionsas the primary MEK activator. B-Raf is one of the most frequentlymutated genes in human cancers. B-Raf kinase represents an excellenttarget for anticancer therapy based on preclinical target validation,epidemiology and drugability. Small molecule inhibitors of B-Raf arebeing developed for anticancer therapy. Examples of small moleculeinhibitors of B-Raf include but are not limited to dabrafenib(Tafinlar®). Nexavar® (sorafenib tosylate) is a multikinase inhibitor,which includes inhibition of B-Raf, and is approved for the treatment ofpatients with advanced renal cell carcinoma and unresectablehepatocellular carcinoma. Other Raf inhibitors have also been disclosedor have entered clinical trials, for example GSK-2118436, RAF-265,vemurafenib (Zelboraf, PLX-4032), PLX3603 and XL-281. Examples of smallmolecule inhibitors of MEK include but are not limited to trametinib(Mekinist®), Other MEK inhibitors include ARRY-886 (AZD6244); 29) Cellcycle signaling inhibitors, including inhibitors of cyclin dependentkinases (CDKs) are also useful in combination with the compounds of thedisclosure in the compositions and methods described above. Examples ofcyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitorsfor the same are described in, for instance, Rosania G. R. et al., Exp.Opin. Ther. Patents (2000) 10 215-230; 30) Inhibitors of phosphatidylinositoi-3-0H kinase family members including blockers of PI3-kinase,ATM, DNA-PK, and Ku may also be useful in combination with the presentdisclosure; 31) Antagonists of smoothened receptor (SMO) may also beuseful in combination with the present disclosure. Examples ofantagonists of smoothened receptor include but are not limited tovismodegib (Erivedge®); 32) Inhibitors of protein translation may alsobe useful in combination with the present disclosure. Examples ofinhibitors of protein translation include but are not limited toomacetaxine mepesuccinate (Synribo®); and 33) anti-cancer agents withother mechanisms of action including miltefosine (Impavido and Miltex),masoprocol, mitoguazone, alitretinoin, mitotane, arsenic trioxide,celecoxib, and anagrelide.

Compounds disclosed herein may also be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound as disclosed herein, alone or with radiation therapy. For theprevention or treatment of emesis, a compound as disclosed herein may beused in conjunction with other anti-emetic agents, especiallyneurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such asondansetron, granisetron, tropisetron, and zatisetron, GABAB receptoragonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In another embodiment, conjunctive therapywith an anti-emesis agent selected from a neurokinin-1 receptorantagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosedfor the treatment or prevention of emesis that may result uponadministration of the instant compounds.

A compound as disclosed herein may also be administered with an agentuseful in the treatment of anemia. Such an anemia treatment agent is,for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound as disclosed herein may also be administered with an agentuseful in the treatment of neutropenia. Such a neutropenia treatmentagent is, for example, a hematopoietic growth factor which regulates theproduction and function of neutrophils such as a human granulocytecolony stimulating factor, (G-CSF). Examples of a G-CSF includefilgrastim.

A compound as disclosed herein may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

A compound as disclosed herein may also be useful for treating cancer incombination with the following therapeutic agents: abarelix (PlenaxisDepot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb(Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®);altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®);arsenic trioxide (Trisenox®); asparaginase (Elspar®); Axitinib(Inlyta®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotenecapsules (Targretin®); bexarotene gel (Targretin®); bicalutamide(Casodex®), bleomycin (Blenoxane®); bortezomib (Velcade®); busulfanintravenous (Busulfex®); busulfan oral (Myleran®); calusterone(Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®);carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine withPolifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®);cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®);cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide(Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®);cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabineliposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin,actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); dasatinib(Sprycel®); daunorubicin liposomal (DanuoXome®); daunorubicin,daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®);Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel(Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®,Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal(Doxil®); doxorubicin liposomal (Doxil®); dromostanolone propionate(Dromostanolone®); dromostanolone propionate (Masterone Injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); flutamide (Eulexin®), fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin Implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); ipilimumab (Yervoy®), irinotecan(Camptosar®); lapatinib (TYKERB®), lenalidomide (Revlimid®); letrozole(Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); panitumumab (VECTIBIX®),pamidronate (Aredia®); Pazopanib (Votrient®), pegademase (Adagen(Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pertuzumab (OMNITARG®, 2C4), pipobroman (Vercyte®); plicamycin,mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine(Matulane®); quinacrine (Atabrine®); Rapamycin (Sirolimus, RAPAMUNE®,),Rasburicase (Elitek®); Rituximab (Rituxan®); rubitecan (Orathecin),ruxolitinib (Jakafi®); sargramostim (Leukine®); Sargramostim (Prokine®);sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate(Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide(Temodar®); temsirolimus (Torisel®); teniposide, VM-26 (Vumon®);testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab(Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab(Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (UracilMustard Capsules®); valrubicin (Valstar®); vandetanib (ZACTIMA®),vemurafenib (Zelboraf®), vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); vorinostat (Zolinza®); zoledronate (Zometa®),nilotinib (Tasigna®); and dasatinib (Sprycel®). ARRY-886 (Mek inhibitor,AZD6244), SF-1126 (PI3K inhibitor,), BEZ-235 (PI3K inhibitor), XL-147(PI3K inhibitor), PTK787/ZK 222584, crizotinib (Xalkori®), andvemurafenib (Zelboraf®).

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, certain embodiments provide methods fortreating disorders and symptoms relating cancer in a human or animalsubject in need of such treatment comprising administering to saidsubject an amount of a compound disclosed herein effective to reduce orprevent said disorder in the subject, in combination with at least oneadditional agent for the treatment of said disorder that is known in theart. In a related aspect, certain embodiments provide therapeuticcompositions comprising at least one compound disclosed herein incombination with one or more additional agents for the treatment ofdisorders and symptoms relating to cancer.

The compounds, compositions, and methods disclosed herein are useful forthe treatment of disease. In certain embodiments, the diseases is one ofdysregulated cellular proliferation, including cancer. The cancer may behormone-dependent or hormone-resistant, such as in the case of breastcancers. In certain embodiments, the cancer is a solid tumor. In otherembodiments, the cancer is a lymphoma or leukemia. In certainembodiments, the cancer is and a drug resistant phenotype of a cancerdisclosed herein or known in the art. Tumor invasion, tumor growth,tumor metastasis, and angiogenesis may also be treated using thecompositions and methods disclosed herein. Precancerous neoplasias arealso treated using the compositions and methods disclosed herein.

Cancers to be treated by the methods disclosed herein include coloncancer, breast cancer, ovarian cancer, lung cancer and prostate cancer;cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx,pharynx), esophagus, stomach, small intestine, large intestine, colon,rectum, liver and biliary passages; pancreas, bone, connective tissue,skin, cervix, uterus, corpus endometrium, testis, bladder, kidney andother urinary tissues, including renal cell carcinoma (RCC); cancers ofthe eye, brain, spinal cord, and other components of the central andperipheral nervous systems, as well as associated structures such as themeninges; and thyroid and other endocrine glands. The term “cancer” alsoencompasses cancers that do not necessarily form solid tumors, includingHodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma andhematopoietic malignancies including leukemias (Chronic LymphocyticLeukemia (CLL), Acute Lymphocytic Leukemia (ALL)) and lymphomasincluding lymphocytic, granulocytic and monocytic. Additional types ofcancers which may be treated using the compounds and methods of thedisclosure include, but are not limited to, adenocarcinoma,angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma,basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma,chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma,endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor,epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tractcancers, glioblastoma multiforme, head and neck cancer,hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma,large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphaticsystem cancer, lymphomas, lymphangiosarcoma,lymphangioendotheliosarcoma, medullary thyroid carcinoma,medulloblastoma, meningioma mesothelioma, myelomas, myxosarcomaneuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma,epithelial ovarian cancer, papillary carcinoma, papillaryadenocarcinomas, paraganglioma, parathyroid tumors, pheochromocytoma,pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceousgland carcinoma, seminoma, skin cancers, melanoma, small cell lungcarcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweatgland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm'stumor.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing tumor invasion and tumormetastasis.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing angiogenesis and disorders relatedto angiogenesis.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Abbreviations

CHCl₃=chloroform; i-PrOH=isopropanol; H₂O=water; DCM=dichloromethane;Na₂SO₄=sodium sulfate; MgSO₄=magnesium sulfate; EtOAc=ethyl acetate;EtOH=ethanol; Et₂O=diethyl ether; THF=tetrahydrofuran;NMP═N-Methyl-2-pyrrolidone; NaOH=sodium hydroxide; MeOH=methanol;CDCl₃=deuterated chloroform; HCl=hydrochloric acid; MeCN=acetonitrile;Cs₂CO₃=cesium carbonate; DMF═N,N-dimethylformamide; CD₃OD=deuteratedmethanol; DMSO-d₆=deuterated dimethyl sulfoxide; DMSO=dimethylsulfoxide; TFA=trifluoroacetic acid; AcOH=acetic acid; HBr=hydrobromicacid; HCOOH=formic acid; K₂CO₃=potassium carbonate;DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; NaHCO₃=sodium hydrogencarbonate; KCN=potassium cyanide; TEA=Et₃N=triethylamine;DMAP=4-dimethylaminopyridine; NH₂OH.HCl=hydroxylammonium chloride;DIEA=N,N-diisopropylethylamine; LiOH=lithium hydroxide; NH₄HCO₃=ammoniumhydrogen carbonate; NH₄OH=ammonium hydroxide; K₃PO₄=potassium phosphatetribasic; NaOtBu=sodium t-butoxide; CuBr₂=copper (II) bromide;CuCl₂=copper (II) chloride; CuCN(LiCl)₂=Copper(I) cyanide di(lithiumchloride) complex; EDC.HCl=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride; HOBT=1-hydroxybenzotriazole;PyBop=(Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; LiCl=lithium chloride; NaI=sodium iodide;NaBr=sodium bromide; N₂=nitrogen; Ar=argon; MnO₂=manganese dioxide;HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium; BH₃-THF=borane tetrahydrofurancomplex solution; POCl₃=phosphorus oxychloride; Ac₂O=acetic anhydride;NH₂NH₂.H₂O=hydrazine hydrate; NaBH₄=sodium borohydride; NaBH₃CN=sodiumcyanoborohydride; n-BuLi=n-butyllithium; CH₃I=methyl iodide; CS₂=carbondisulfide; AIBN=azobisisobutyronitrile; KF=potassium fluoride;Bu₃SnH=tributyltin hydride;RuPhos=2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl;XPhos=2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; andPd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0);Pd(Ph₃)₄=tetrakis(triphenylphosphine)palladium(0);NCS═N-chlorosuccinimide; DEAD=diethyl azodicarboxylate; O₅O₄=osmiumtetraoxide; DIBAL-H=di-iso-butyl aluminum hydride; t-BuOH=tert-butanol;Py=pyridine; NaOMe=sodium methoxide; prep-HPLC=preparativehigh-performance liquid chromatography.

Compounds

The present disclosure provides a compound of structural Formula I(R₁)_(n)-A-Y₁—B-D-E-(R₃)_(p).(M)_(a).(H₂O)_(b)   (I)wherein: M is selected from an inorganic acid, an organic acid, a basicamino acid, or an acidic amino acid with the proviso that M is nottrifluoroacetic acid; a is a fractional or whole number between about0.5 and about 3.5 inclusive; b is a fractional or whole number betweenabout 0 and about 5 inclusive; n is 0, 1, or 2; p is 0, 1, or 2; q is 0,1, 2, 3, or 4; u is 0, 1, or 2; A is selected from aryl or heteroaryl; Bis selected from

D is selected from alkyl, heteroalkyl, alkoxy, alkylthio, carbonyl,alkylcarbonyl, carboxyl, oxy, thio, sulfinyl, sulfonyl, sulfonamido,amino, amido, alkylamino, or heteroaryl, any of which can be optionallysubstituted with one or more substituents selected from hydrogen,deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, heteroalkyl,hydroxyalkyl, acyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or oxo, any of which maybe optionally substituted; E is selected from aryl or heteroaryl; G isselected from saturated 3- to 7-membered cycloalkyl or saturated 3- to7-membered heterocycloalkyl; R₁ is selected from —Y₂-alkyl-N(R₄)R₅,hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl,carboxylalkyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, alkylthio, thiolalkyl, mercaptyl, thiol, sulfonate,sulfonamido, alkylsulfonyl, amino, amido, alkylamino, dialkylamino,carbamate, nitro, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl,heteroarylcarbonyl, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl,heterocycloalkylcarbonylalkyl, or heteroarylalkyl, any of which can beoptionally substituted with one or more substituents selected fromhydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, amidoalkyl, acyl, carbonyl,carboxyl, carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl,hydroxyalkylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, alkoxyalkyl, carboxyl, cyano, hydroxy,alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio, thiol, acylthio,sulfonamido, alkylsulfonyl, amino, amido, carbamate, alkylamino,dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, nitro, trisubstitutedsilyl, trisubstituted siloxy, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, alkylheterocycloalkyl, any of which may be optionallysubstituted; R₃ is selected from hydrogen, deuterium, halogen, alkyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, acyl, carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy,alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo,alkylthio, mercaptyl, thiol, haloalkylthio, perhaloalkylthio,cyanoalkylthio, haloalkylsulfonyl, alkylsulfonyl, alkoxyalkylsulfonyl,cyanoalkylsulfonyl, sulfonate, sulfonamido, amino, amido, alkylamino,dialkylamino, carbamate, nitro, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, or heteroarylalkyl,trisubstituted silyl, —SF₅, —(C(R₃₁)(R₃₂))_(u)—O-alkyl,—(C(R₃₁)(R₃₂))_(u)—O-cycloalkyl, —S(O)_(u)-alkyl, —S(O)_(u)-cycloalkyl,cycloalkylthio, —CF₃, —OCF₃, —(C(R₃₁)(R₃₂))_(u)—OCF₃, saturatedheterocycloalkyloxy, —(C(R₃₁)(R₃₂))_(u)—O-saturated heterocycloalkyl,—(C(R₃₁)(R₃₂))_(u)— saturated heterocycloalkyl, saturatedheterocycloalkylthio, —S(O)_(u)-saturated heterocycloalkyl,—(C(R₃₁)(R₃₂))_(u)—OCF₃,

any of which may be optionally substituted; R₄ and R₅ are independentlyselected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl,alkoxy, haloalkoxy, perhaloalkoxy, alkylsulfonyl, sulfonamido, amido,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkylalkyl,arylalkyl, heterocycloalkylalkyl, or heteroarylalkyl, or R₄ and R₅,taken together, form a heterocyloalkyl or heteroaryl, any of which canbe optionally substituted with one or more substituents selected fromhydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio,mercaptyl, thiol, sulfonate, sulfonamido, amino, amido, alkylamino,dialkylamino, carbamate, nitro, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, or heteroarylalkyl,any of which may be optionally substituted; each R₂₃ is independentlyselected from hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl, carbonyl,carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo,alkylthio, amino, alkylamino, dialkylamino, nitro, cycloalkyl, aryl, orheteroaryl, any of which may be optionally substituted; R₃₁, R₃₂, R₃₃,R₃₄, and R₃₆ are independently selected from hydrogen, deuterium, alkyl,or perfluoroalkyl, any of which can be optionally substituted; R₃₅ isselected from hydrogen, deuterium, alkyl, perfluoroalkyl, cycloalkyl, orsaturated heterocycloalkyl, any of which can be optionally substituted;R₃₇ and R₃₈ are independently selected from alkyl or perfluoroalkyl, orR₃₇ and R₃₈, taken together, form a heterocyloalkyl, any of which can beoptionally substituted; Y₁ is selected from alkyl, alkenyl, alkynyl,heteroalkyl, alkoxy, alkylthio, carbonyl, alkylcarbonyl, carboxyl, oxy,thio, sulfinyl, sulfonyl, sulfonamido, amino, amido, alkylamino, orcarbamate, any of which can be optionally substituted with one or moresubstituents selected from hydrogen, deuterium, halogen, alkyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl,carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, alkylthio, amino, alkylamino, dialkylamino, or cycloalkyl, any ofwhich may be optionally substituted; Y₂ is selected from a bond,carbonyl, alkylcarbonyl, carboxyl, oxy, thio, sulfinyl, sulfonyl,sulfonamido, amino, amido, alkylamino, or carbamate, any of which can beoptionally substituted with one or more substituents selected fromhydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio,mercaptyl, thiol, sulfonate, sulfonamido, amino, amido, alkylamino,dialkylamino, carbamate, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,cycloalkyloxy, aryloxy, heterocycloalkyloxy, heteroaryloxy,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, or heteroarylalkyl,any of which may be optionally substituted; if A is phenyl, B is not

wherein Q₂ or Q₃ are freely substituted; if A is phenyl or pyridyl, Y₁is CH₂, B is

and Q₁ is methyl, ethyl, or trifluoromethyl, then D is not

and wherein * represents the point of attachment to Y₁ and ** representsthe point of attachment to D, and # represents the point of attachmentto B and ## represents the point of attachment to E.

In some embodiments, A is selected from aryl or mono- or bicyclicheteroaryl; B is selected from

D is selected from amido, 5-membered heteroaryl, or 6-memberedheteroaryl, any of which can be optionally substituted with one or moresubstituents selected from hydrogen, deuterium, halogen, alkyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, cyano,hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, or oxo, any of which may be optionallysubstituted; E is selected from phenyl, 5-membered heteroaryl,6-membered heteroaryl, or 9-membered bicyclic heteroaryl; R₄ and R₅ areindependently selected from hydrogen, deuterium, alkyl, alkenyl,alkynyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl,carbonyl, carboxyl, alkoxy, haloalkoxy, perhaloalkoxy, alkylsulfonyl,sulfonamido, amido, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, or heteroarylalkyl,or R₄ and R₅, taken together, form a heterocyloalkyl or heteroaryl, anyof which can be optionally substituted with one or more substituentsselected from hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl,cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio,mercaptyl, thiol, sulfonamido, amino, amido, alkylamino, dialkylamino,carbamate, or cycloalkyl, any of which may be optionally substituted;R₂₃ is selected from hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, alkylthio, amino, alkylamino, dialkylamino,cycloalkyl, aryl, or heteroaryl; Y₁ is alkyl, which can be optionallysubstituted with one or more substituents selected from hydrogen,deuterium, alkyl, cycloalkyl, or halogen; and Y₂ is selected from abond, carbonyl, alkylcarbonyl, carboxyl, oxy, thio, sulfinyl, sulfonyl,sulfonamido, amino, amido, alkylamino, or carbamate, any of which can beoptionally substituted with one or more substituents selected fromhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, acyl, carbonyl, carboxyl, cyano, hydroxy,alkoxy, haloalkoxy, perhaloalkoxy, oxo, alkylthio, mercaptyl, thiol,sulfonamido, amino, amido, alkylamino, dialkylamino, carbamate, orcycloalkyl, any of which may be optionally substituted.

In particular embodiments, B is

In some embodiments, D is selected from —C(═O)NR₁₁—, 5-memberedheteroaryl, or 6-membered heteroaryl; E is selected from phenyl,pyrimidine, 1,3-benzodioxol, indole, or 1-benzofuran; R₁ is selectedfrom —Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium, halogen, alkyl, alkenyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl,carboxylalkyl, carbonyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, alkylthio, thiolalkyl, sulfonamido, alkylsulfonyl,amino, amido, alkylamino, dialkylamino, nitro, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, cycloalkyloxy, aryloxy,heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, orheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from hydrogen,deuterium, halogen, alkyl, alkenyl, alkynyl, amidoalkyl, acyl,carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl, hydroxyalkylcarbonyl,aminoalkylcarbonyl, alkylaminoalkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted; R₃ is selected fromhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylamino, acyl,carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio,haloalkylthio, perhaloalkylthio, cyanoalkylthio, alkylsulfonyl,alkoxyalkylsulfonyl, cyanoalkylsulfonyl, haloalkylsulfonyl, sulfonamido,alkylsulfonamido, amino, alkylamino, dialkylamino, amido, cycloalkyl,aryl, heterocycloalkyl, heteroaryl perhaloalkylcycloalkyl,hydroxyheterocycloalkyl, hydroxycycloalkyl, heterocycloalkylcarbonyl, orheterocycloalkylalkyl, any of which can be optionally substituted; R₁₁is selected from hydrogen, deuterium, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, cycloalkyl, aryl, heterocycloalkyl, orheteroaryl, any of which may be optionally substituted; Y₁ is —CH₂—; andY₂ is selected from a bond, carbonyl, amino, or alkylamino.

In some embodiments, A is selected from phenyl, 5-membered heteroaryl,or 6-membered heteroaryl; E is phenyl; R₁ is selected from—Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium, halogen, alkyl, alkenyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, acyl, carboxylalkyl,carboxyl, carbonyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,oxo, thiolalkyl, sulfonyl, sulfonamido, alkylsulfonyl, amino, amido,alkylamino, dialkylamino, nitro, heterocycloalkyl, heterocycloalkyloxy,

heterocycloalkylcarbonylalkyl, or heterocycloalkylcarbonyl, any of whichcan be optionally substituted with one or more substituents selectedfrom hydrogen, deuterium, halogen, alkyl, alkenyl, amidoalkyl, acyl,carboxylalkyl, hydroxyalkylcarbonyl, alkynylcarbonyl, heteroalkyl,hydroxyalkyl, alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, oxo,sulfonamido, alkylsulfonyl, amino, amido, carbamate, dialkylamino,dialkylaminoalkyl, trisubstituted siloxy, cycloalkyl, heterocycloalkyl,alkylheterocycloalkyl, any of which may be optionally substituted; R₁₁is selected from hydrogen, deuterium, alkyl, or cycloalkyl, any of whichmay be optionally substituted; and each R₂₃ is independently selectedfrom hydrogen, deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl,cyano, saturated 3- to 6-membered cycloalkyl, 4- to 6-memberedheterocycloalkyl, or 5- to 6-membered heteroaryl.

In particular embodiments, n is 1; p is 1; and R₂₃ is selected fromalkyl, haloalkyl, perhaloalkyl, hydroxy, or cyclopropyl.

In some embodiments, the compound has structural Formula II

wherein: M is selected from the group consisting of an inorganic acid,an organic acid, a amino acid; with the proviso that M is nottrifluoroacetic acid; a is a fractional or whole number between about0.5 and about 3.5 inclusive; b is a fractional or whole number betweenabout 0 and about 10 inclusive;X₂, X₄, and X₅ are independently selected from CR₂₁, N, O, or S, andwherein X₂, X₄, and X₅, taken together, form a 5-membered heteroaryl; Z₁and Z₂ are independently selected from N, NR₁, C═O, or CR₁; Z₃ isselected from N, NR₁₂, C═O, or CR₁₂; R₁ is selected from—Y₂-alkyl-N(R₄)R₅, hydrogen, deuterium, halogen, alkyl, alkenyl,haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, acyl,carboxylalkyl, carbonyl, carboxyl, carbonyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, oxo, alkylthio, thiolalkyl, sulfonyl,sulfonamido, alkylsulfonyl, amino, amido, alkylamino, dialkylamino,nitro, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyloxy,aryloxy, heterocycloalkyloxy, heteroaryloxy,

cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl, orheterocycloalkylcarbonylalkyl, any of which can be optionallysubstituted with one or more substituents selected from hydrogen,deuterium, halogen, alkyl, alkenyl, alkynyl, amidoalkyl, acyl,carboxylalkyl, alkylcarbonyl, heteroalkylcarbonyl, hydroxyalkylcarbonyl,aminoalkylcarbonyl, alkylaminoalkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, haloalkyl, perhaloalkyl, heteroalkyl, hydroxyalkyl,alkoxyalkyl, carboxyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, oxo, thiol, acylthio, sulfonamido, alkylsulfonyl, amino,amido, carbamate, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, trisubstituted silyl, trisubstituted siloxy,cycloalkyl, aryl, heterocycloalkyl, heteroaryl, alkylheterocycloalkyl,any of which may be optionally substituted; R₁₂, R₁₃, or R₁₄ areindependently selected from hydrogen, deuterium, halogen, alkyl,haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkylthio, amino, or saturated 3- to 7-memberedcycloalkyl, any of which may be optionally substituted; R₁₆, R₁₉, or R₂₀are independently selected from hydrogen, deuterium, halogen, alkyl,haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkylthio, amino, or cycloalkyl, any of which may beoptionally substituted; R₁₇ or R₁₈ are independently selected fromhydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl,heteroalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylamino, acyl,carbonyl, carboxyl, cyano, cyanoalkyl, hydroxy, alkoxy, haloalkoxy,perhaloalkoxy, alkoxyalkoxy, hydroxyalkoxy, oxo, alkylthio,haloalkylthio, perhaloalkylthio, cyanoalkylthio, alkylsulfonyl,alkoxyalkylsulfonyl, cyanoalkylsulfonyl, haloalkylsulfonyl, sulfonamido,alkylsulfonamido, amino, alkylamino, dialkylamino, amido, cycloalkyl,aryl, heterocycloalkyl, heteroaryl perhaloalkylcycloalkyl,hydroxyheterocycloalkyl, hydroxycycloalkyl, heterocycloalkylcarbonyl, orheterocycloalkylalkyl, any of which can be optionally substituted; R₂₁is selected from null, hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, heteroalkyl, hydroxyalkyl, cyano, hydroxy, alkoxy,haloalkoxy, perhaloalkoxy, alkylthio, amino, alkylamino, ordialkylamino; and R₂₃ is selected from hydrogen, deuterium, hydroxyl,alkyl, haloalkyl, perhaloalkyl, cyano, saturated 3- to 6-memberedcycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 6-memberedheteroaryl.

In particular embodiments, two of X₂, X₄, and X₅ are N; and one of X₂,X₄, and X₅ is O; or one of X₂, X₄, and X₅ is N; one of X₂, X₄, and X₅ isO; and one of X₂, X₄, and X₅ is CH; and R₂₃ is selected from hydrogen,deuterium, hydroxyl, alkyl, haloalkyl, perhaloalkyl, cyano, or saturated3- to 6-membered cycloalkyl.

In particular embodiments, R₁ is selected from hydrogen, deuterium,fluorine, bromine, cyano, methyl, isopropyl,

ethylene,

trifluoromethyl, bromomethyl, hydroxymethyl, difluoromethoxy, methoxy,ethoxy, isopropoxy, hydroxy, nitro, acetyl, carboxyl, —CO₂CH₃,

—SO₂CH₃, —SO₂CH₂CH₃, SO₂CH₂CH₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

R₁₈ is selected from hydrogen, deuterium, halogen, methyl, isopropyl,tert-butyl, cyclopropyl, cyclohexyl, acetyl, hydroxymethyl,methoxymethyl, methoxy, isopropoxy, methylamino, dimethylamino,methylthio, cyanomethyl, cyanomethylthio, cyano, —SO₂CH₃, —SO₂CH(CH₃)₂,—SO₂CH₂CH(CH₃)₂, —SO₂NHCH₂CH₂CH₃, —SO₂CHF₂, —SO₂CF₃,

trifluoromethyl, trifluoromethylthio, difluoromethoxy, ortrifluoromethoxy; R₂₂ is selected from hydrogen, deuterium, methyl,acetyl,

and R₂₃ is selected from hydrogen, deuterium, methyl, ethyl, 3-pyridyl,or cyclopropyl

In particular embodiments, R₁ is selected from hydrogen, halogen, cyano,methyl, isopropyl,

ethylene, trifluoromethyl, difluoromethoxy, methoxy, ethoxy, isopropoxy,hydroxy, carboxyl, —CO₂CH₃, —SO₂CH₃, —SO₂NH₂,

amino, methylamino, dimethylamino,

and R₂₃ is methyl.

In particular embodiments, two of X₂, X₄, and X₅ are N; and one of X₂,X₄, and X₅ is O.

In particular embodiments, one of X₂, X₄, and X₅ is N; one of X₂, X₄,and X₅ is O; and one of X₂, X₄, and X₅ is CH.

In some embodiments, the compound has structural Formula III:

wherein: M is selected from the group consisting of an inorganic acid,an organic acid, an amino acid; with the proviso that M is nottrifluoroacetic acid; a is a fractional or whole number between about0.5 and about 3.5 inclusive; b is a fractional or whole number betweenabout 0 and about 10 inclusive; X₂ and X₄ are N and X₅ is O; X₄ and X₅are N and X₂ is O; X₂ and X₅ are N and X₄ is O; X₂ is CH, X₄ is N, andX₅ is O; or X₂ is CH, X₄ is O, and X₅ is N; Z₂ is selected from N orCR₁₄; R₁ is selected from heterocycloalkyl, alkoxyalkoxy,alkylsulfonylalkoxy, heterocycloalkyloxy, heterocycloalkylcarbonyl,alkoxyalkylamido, heterocycloalkylsulfonyl, alkoxyalkylsulfonamido,wherein said heterocycloalkyl, heterocycloalkyloxy,heterocycloalkylcarbonyl, or heterocycloalkylsulfonyl can be optionallysubstituted with one or more substituents selected from the groupconsisting hydrogen, alkyl, or oxo; R₁₄, R₃₉, and R₄₀ are independentlyselected from hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,alkylthio, amino, or saturated 3- to 7-membered cycloalkyl, any of whichmay be optionally substituted; or R₁₈ is selected from alkyl, haloalkyl,perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio,haloalkylthio, or perhaloalkylthio.

In some embodiments, M has a pKa of less than about 2.4.

In certain embodiments, R₁ is selected from

In particular embodiments, R₁₈ is selected from isopropyl, tert-butyl,—CF₃, —OCF₃, —OCHF₂, or —SCF₃.

In particular embodiments, R₁ is selected from

R₁₃, R₁₄, R₁₆, R₁₇, and R₁₉ are hydrogen; and R₁₈ is selected fromisopropyl, tert-butyl, —CF₃, —OCF₃, —OCHF₂, or —SCF₃.

In certain embodiments, the compound is in a solid form. In particularembodiments, the compound is in a crystalline form.

In some embodiments, M is selected from hydrochloric acid, hydroboricacid, nitric acid, sulfuric acid, phosphoric acid, lactic acid, formicacid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid,glycine, aspartic acid or glutamic acid. In certain embodiments, M isselected from hydrochloric acid, benzenesulfonic acid, ormethanesulfonic acid.

In some embodiments, M has a pKa of less than about 2.4.

In some embodiments, a equals 1 and M is hydrochloric acid

In some embodiments, a equals 1 and M is benzenesulfonic acid.

In some embodiments, a equals 1 and M is methanesulfonic acid.

In some embodiments, the compound is5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride;5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole2,2,2-trifluoroacetate;5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemethanesulfonate; or5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolebenzenesulfonate.

In some embodiments, the compound has structural Formula V

wherein M is selected from (+)-camphor-10-sulfonic acid,2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, acetic acid,aspartic acid, benzenesulfonic acid, citric acid, cyclamic acid,di(tert-butyl) naphthalenesulfonic acid, dodecylsulfonic acid,ethanesulfonic acid, formic acid, fumaric acid, glutamic acid,glycerophosphoric acid, glycine, hydroboric acid, hydrobromic acid,hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonicacid, naphthalene-2-sulfonic acid, nitric acid, oxalic acid, phosphoricacid, p-toluenesulfonic acid, pyruvic acid, saccharine, succinic acid,sulfuric acid, tartaric acid, and thiocyanic acid; a is a fractional orwhole number between about 0.5 and about 3.5 inclusive; and b is afractional or whole number between about 0 and about 10 inclusive.

In some embodiments, b is a fractional or whole number between about 0and about 5 inclusive.

A compound of Formula V

wherein M is selected from the group consisting of hydrochloric acid,di(tert-butyl) naphthalenesulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic acid, cyclamic acid, p-toluenesulfonic acid,thiocyanic acid, nitric acid, methanesulfonic acid, dodecylsulfonicacid, naphthalene-2-sulfonic acid, benzenesulfonic acid, oxalic acid,saccharine, 2,2-dichloroacetic acid, glycerophosphoric acid, phosphoricacid, (+)-camphor-10-sulfonic acid, sulfuric acid, maleic acid, andpyruvic acid;a is a fractional or whole number between about 0.5 and about 3.5inclusive; andb is a fractional or whole number between about 0 and about 10inclusive.

In some embodiments, b is a fractional or whole number between about 0and about 5 inclusive.

In some embodiments, M is chosen from hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, nitric acid, methanesulfonic acid,benzenesulfonic acid, oxalic acid, and maleic acid.

In some embodiments, M is chosen from hydrochloric acid, methanesulfonicacid, and benzenesulfonic acid.

In some embodiments, a is a number between 1 and 2 inclusive; and b is anumber between 0 and about 2 inclusive.

In particular embodiments, a equals 1 and M is hydrochloric acid.

In particular embodiments, a equals 1 and M is benzenesulfonic acid.

In particular embodiments, a equals 1 and M is methanesulfonic acid.

Also provided are embodiments wherein any embodiment above in paragraphs[0178]-[0212] above may be combined with any one or more of theseembodiments, provided the combination is not mutually exclusive. As usedherein, two embodiments are “mutually exclusive” when one is defined tobe something which cannot overlap with the other. For example, anembodiment wherein M is methanesulfonic acid is mutually exclusive withan embodiment wherein M is hydrochloric acid. However, an embodimentwherein R¹ is chosen from a particular group of substituents is notmutually exclusive with an embodiment wherein M is hydrochloric acid.

In some embodiments, the compound has structural Formula VI:

wherein X is chosen from chloride, naphthalene-1,5 disulfonate,di(tert-butyl) naphthalenesulfonate, sulfate, ethane-1,2-disulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, cyclamate, tosylate,thiocyanate, nitrate, mesylate, dodecylsulfonate,naphthalene-2-sulfonate, trifluoroacetate, besylate, oxalate,saccharate, 2,2-dichloroacetate, glycerophosphorate, maleate,phosphorate, (+)-camphoor-10-sulfonate, and pyruvate.

In some embodiments, X is chosen from chloride, sulfate, tosylate,nitrate, mesylate, besylate, and maleate.

In some embodiments, X is chosen from chloride, mesylate, and besylate.In some embodiments, X is chosen from chloride and mesylate. In someembodiments, X is chloride. In some embodiments, X is mesylate.

Also provided are embodiments wherein any embodiment above in paragraphs[0214]-[0216] above may be combined with any one or more of theseembodiments, provided the combination is not mutually exclusive.

In some embodiments, the compound is chosen from5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride,5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole2,2,2-trifluoroacetate,5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemethanesulfonate, and5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolebenzenesulfonate. In some embodiments, the compound is5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride. In some embodiments, the compound is5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole2,2,2-trifluoroacetate. In some embodiments, the compound is5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemethanesulfonate. In some embodiments, the compound is5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolebenzenesulfonate.

Pharmaceutical Compositions, Methods of Treatment, and Preparation ofMedicaments

Also provided herein is a pharmaceutical composition comprising acompound as disclosed herein, together with a pharmaceuticallyacceptable carrier.

Also provided herein is a method of treatment of a HIF pathway-mediateddisease comprising the administration of a therapeutically effectiveamount of a compound as disclosed herein to a patient in need thereof.

In some embodiments, said disease is cancer.

In some embodiments, said cancer is selected from the group consistingof colon cancer, breast cancer, ovarian cancer, lung cancer, prostatecancer; cancers of the oral cavity and pharynx (lip, tongue, mouth,larynx, pharynx), esophagus, stomach, small intestine, large intestine,colon, rectum, liver and biliary passages; pancreas, bone, connectivetissue, skin, cervix, uterus, corpus endometrium, testis, bladder,kidney and other urinary tissues, including renal cell carcinoma (RCC);cancers of the eye, brain, spinal cord, and other components of thecentral and peripheral nervous systems, as well as associated structuressuch as the meninges; cancers of the thyroid and other endocrine glands;Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma,hematopoietic malignancies including leukemias (Chronic LymphocyticLeukemia (CLL), Acute Lymphocytic Leukemia(ALL)) and lymphomas includinglymphocytic, granulocytic and monocytic; adrenocarcinoma, angiosarcoma,astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cellcarcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma,craniopharyngioma, cutaneous melanoma, cystadenocarcinoma,endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor,epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tractcancers, glioblastoma multiforme (also called simply “glioblastoma”),head and neck cancer, hemangioblastoma, hepatocellular carcinoma,hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma,leukemias, liposarcoma, lymphatic system cancer, lymphomas,lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroidcarcinoma, medulloblastoma, meningioma mesothelioma, myelomas,myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma,osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma,papillary adenocarcinomas, paraganglioma, parathyroid tumors,pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma,rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers,melanoma, small cell lung carcinoma, non-small cell lung carcinoma,squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroidcancer, uveal melanoma, and Wilm's tumor. In some embodiments, thecancer is glioblastoma. In some embodiments, the cancer isneuroblastoma. In some embodiments, the cancer is lymphoma. In someembodiments, the cancer is diffuse large B-cell lymphoma.

Also provided herein is a method of treatment of a disease caused byabnormal cell proliferation comprising the administration of atherapeutically effective amount of a compound as disclosed herein to apatient in need thereof.

Also provided herein is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein to a patient, wherein the effect isselected from the group consisting of preventing or reducing resistanceto radiotherapy and chemotherapy, preventing or reducing tumor invasionand tumor metastasis, and preventing or reducing angiogenesis.

In the embodiments above in paragraphs [0219]-[0224], compoundsdisclosed herein include, without limitation, any embodiment above inparagraphs [0178]-[0218].

Also provided herein is the use of a compound as disclosed herein in thetreatment of, or in the preparation of a medicament for the of treatmentof, a HIF pathway-mediated disease comprising the administration of atherapeutically effective amount.

In some embodiments, said disease is cancer.

In some embodiments, said cancer is selected from the roup consisting ofcolon cancer, breast cancer, ovarian cancer, lung cancer, prostatecancer; cancers of the oral cavity and pharynx (lip, tongue, mouth,larynx, pharynx), esophagus, stomach, small intestine, large intestine,colon, rectum, liver and biliary passages; pancreas, bone, connectivetissue, skin, cervix, uterus, corpus endometrium, testis, bladder,kidney and other urinary tissues, including renal cell carcinoma (RCC);cancers of the eye, brain, spinal cord, and other components of thecentral and peripheral nervous systems, as well as associated structuressuch as the meninges; cancers of the thyroid and other endocrine glands;Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma,hematopoietic malignancies including leukemias (Chronic LymphocyticLeukemia (CLL), Acute Lymphocytic Leukemia(ALL)) and lymphomas includinglymphocytic, granulocytic and monocytic; adrenocarcinoma, angiosarcoma,astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cellcarcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma,craniopharyngioma, cutaneous melanoma, cystadenocarcinoma,endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor,epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tractcancers, glioblastoma multiforme (also called simply “glioblastoma”),head and neck cancer, hemangioblastoma, hepatocellular carcinoma,hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma,leukemias, liposarcoma, lymphatic system cancer, lymphomas,lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroidcarcinoma, medulloblastoma, meningioma mesothelioma, myelomas,myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma,osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma,papillary adenocarcinomas, paraganglioma, parathyroid tumors,pheochromocytoma, pinealoma, plasmacytomas, retinoblastoma,rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancers,melanoma, small cell lung carcinoma, non-small cell lung carcinoma,squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroidcancer, uveal melanoma, and Wilm's tumor. In some embodiments, thecancer is glioblastoma. In some embodiments, the cancer isneuroblastoma. In some embodiments, the cancer is lymphoma. In someembodiments, the cancer is diffuse large B-cell lymphoma.

Also provided herein is the use of a compound as disclosed herein in thetreatment of, or in the preparation of a medicament for the of treatmentof, a disease caused by abnormal cell proliferation.

Also provided herein is the use of a compound as disclosed herein, or inthe preparation of a medicament, for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein to a patient, wherein the effect isselected from the group consisting of preventing or reducing resistanceto radiotherapy and chemotherapy, preventing or reducing tumor invasionand tumor metastasis, and preventing or reducing angiogenesis.

In the embodiments above in paragraphs [0226]-[0230], compoundsdisclosed herein include, without limitation, any embodiment above inparagraphs [0178]-[0218].

The disclosure is further illustrated by the following examples, whichmay be made by methods known in the art and/or as shown below.

Synthesis

Compounds

Compounds according to Formula I may be made from the followingExamples, which may be made by methods known in the art, and/or as shownbelow, and/or as disclosed in U.S. application Ser. No. 13/974,258,filed Aug. 23, 2013, the disclosure of which is hereby incorporated byreference as if written herein in its entirety.

EXAMPLE 804-Methanesulfonyl-1-{3-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-1,2,4-triazol-1-yl)methyl]phenyl}piperidine

Step 1 3-(4-(Trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide

To the solution of ethyl3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (13.6 g,45.0 mmol) in EtOH (200 mL), NH₂NH₂.H₂O (80%, 14 mL, 225 mmol) wasadded. The reaction mixture was stirred at RT overnight. The desiredcompound precipitated from the reaction mixture, filtered and washedwith EtOH (50 mL) to afford3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide as alight yellow solid (9.7 g, 75%). MS (ES+) C₁₀H₇F₃N₄O₃ requires: 288.found: 289 [M+H]⁺.

Step 25-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

To a solution of3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (9.7 g,33.7 mmol) and acetimidamide hydrochloride (4.8 g, 50.5 mmol) in dry THF(300 mL), NaOH (2.0 g, 50.5 mmol) was added at RT. The mixture wasrefluxed overnight. The solution was cooled, concentrated andethane-1,2-diol (100 mL) was added. The resulting mixture was heated at180° C. for 3 h, cooled to RT, diluted with H₂O (800 mL), and extractedwith EtOAc (3×400 mL). The combined organic layers were washed with H₂O(300 mL) and brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the crude solid product,which was treated with EtOAc (150 mL). The resulting suspension wasstirred at RT for 15 min, and then filtered to afford 4.8 g of the puredesired compound. The remaining filtrate was concentrated and purifiedby silica gel column chromatography (Petroleum ether:EtOAc=1:1) toafford 1.4 g of another batch of5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleas a white solid-overall 6.2 g, yield 59%. MS (ES+) C₁₂H₈F₃N₅O₂requires: 311. found: 312 [M+H]⁺.

Step 35-(1-(3-Bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole(100 mg, 0.321 mmol) was placed in THF (3 mL) and K₂CO₃ (66 mg, 0.482mmol) was added. The reaction was stirred for 5 min and1-bromo-4-(bromomethyl)benzene (84 mg, 0.338 mmol) was added. Thereaction was stirred at 50° C. overnight and was then partitionedbetween H₂O (15 mL) and EtOAc (15 mL). The organic layer was separated,washed with H₂O (2×10 mL) and brine (10 mL), dried over Na₂SO₄,filtered, and concentrated to afford the crude product which waspurified by silica gel chromatography (EtOAc/Hexane 10%-100% EtOAc) toafford5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleas a white solid (82 mg, 53%). MS (ES+) C₁₉H₁₃BrF₃N₅O₂ requires: 479,481 found 480 [M+H]⁺, 482 [M+2+H]⁺ (1:1); ¹H NMR (600 MHz, CDCl₃) δ 8.28(d, J=8.8 Hz, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=8.8Hz, 2H), 7.26 (d, J=7.6 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H), 5.43 (s, 2H),2.55 (s, 3H).

Step 44-Methanesulfonyl-1-{3-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-1,2,4-triazol-1-yl)methyl]phenyl}piperidine

A mixture of5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole(165 mg, 0.34 mmol), 4-(methylsulfonyl)piperidine (62 mg, 0.38 mmol),and Cs₂CO₃ (224 mg, 0.69 mmol) in toluene (2 mL) was degassed with argonfor 5 min. Pd₂(dba)₃ (0.15 mg, 0.017 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (33mg, 069 mmol) were added and the reaction mixture was degassed a secondtime with argon for 5 min, then heated to 140° C. for 18 h. The mixturewas then cooled to RT, diluted with EtOAc (15 mL), filtered through apad of Celite, and concentrated under reduced pressure. The crudeproduct was purified by prep-HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=40%-80% in 12 min; Column: C18) to give the titlecompound as a white solid; MS (ES+) C₂₅H₂₅F₃N₆O₄S requires: 562. found:563 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 8.22 (d, J=8.8 Hz, 2H), 7.61 (d,J=8.2 Hz, 2H), 7.21 (t, J=7.9 Hz, 1H), 6.97 (bs, 1H), 6.94 (dd, J=8.3,2.4 Hz, 1H), 6.64 (d, J=7.5 Hz, 1H), 5.48 (s, 2H), 3.86 (bd, J=13.4 Hz,2H), 3.28 (m, 1H), 2.94 (s, 3H), 2.76 (m, 2H), 2.57 (s, 3H), 2.06 (bd,J=13.4 Hz, 2H), 1.68 (ddd, J=16.5, 12.5, 4.1 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −56.6.

Additional compounds from which salts may be made include:

Salts

The method is directed to chemistry involved in the synthesis of saltsand/or hydrates of the heterocycles described herein. One of skill inthe art would understand that the disclosed salts can be made in avariety of ways that may differ from the exemplary scheme describedbelow. Acid addition salts of the compounds of formula I can be preparedin a standard manner in a suitable solvent from the parent compound andan excess of an acid, such as (+)-camphor-10-sulfonic acid,2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 4-amino salicylicacid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzoicacid, benzenesulfonic acid, camsylate, capric acid, caproic acid,caprylic acid, cinnamic acid, citric acid, cyclamic acid, di(tert-butyl)naphthalenesulfonic acid, dodecylsulfonic acid, ethanesulfonic acid,formic acid, fumaric acid, gentisic acid, glutamic acid,glycerophosphoric acid, glutaric acid, glycine, hydroboric acid,hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid,lauric acid, maleic acid, malic acid, malonic acid, mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid, nitric acid, oxalicacid, phosphoric acid, propionic acid, p-toluenesulfonic acid,pyroglutamic acid, pyruvic acid, saccharine, salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tartaric acid, andthiocyanic acid. Certain of the compounds form inner salts orzwitterions that may be acceptable.

EXAMPLE 164 Preparation of Salts5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride

5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride

To a solution of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole(2.67 g, 4.75 mmol) in DCM (50 mL) was added HCl (1 M in Et₂O) (4.79 ml,4.79 mmol) and the resulting mixture was stirred at 50° C. for 1 h. Thereaction mixture was allowed to cool to room temperature and the solidwas collected by vacuum filtration to give1-(3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenyl)-4-(methylsulfonyl)piperidin-1-iumchloride (2.68 g, 4.47 mmol, 94% yield). ¹H NMR (600 MHz, CDCl₃) δ 8.28(d, J=8.7 Hz, 2H), 8.01 (brs, 1H), 7.70-7.62 (m, 1H), 7.57-7.50 (m, 1H),7.37-7.28 (m, 3H), 5.49 (s, 2H), 3.94 (app brs, 2H), 3.42 (app brs, 2H),3.25 (brs, 1H), 3.02 (s, 3H), 2.96 (app brs, 2H), 2.77 (app brs, 2H),2.64 (s, 3H).

1-(3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenyl)-4-(methylsulfonyl)piperidin-1-iumbenzenesulfonate (besylate)

To a solution of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole(100 mg, 0.178 mmol) in DCM (1778 μl) was added benzenesulfonic acid(29.5 mg, 0.187 mmol) and the resulting mixture was stirred at 50° C.for 1 h. The reaction mixture was allowed to cool to room temperatureand the volatiles were removed under reduced pressure. The solid wascollected, triturated with ether (3×2 mL), and dried under reducedpressure to give1-(3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenyl)-4-(methylsulfonyl)piperidin-1-iumbenzenesulfonate (120 mg, 94%). ¹H NMR (600 MHz, CDCl₃) δ 12.67 (brs,1H), 8.26 (d, J=8.7 Hz, 2H), 7.96-7.87 (m, 3H), 7.64-7.56 (brs, 1H),7.53-7.46 (m, 1H), 7.46-7.40 (m, 3H), 7.39-7.31 (m, 3H), 5.41 (s, 2H),4.07-3.75 (app brs, 2H), 3.73-3.56 (app brs, 2H), 3.51-3.38 (brs, 1H),3.14-2.85 (app brs, 3H), 2.84-2.64 (app brs, 2H), 2.60-2.39 (app brs,4H), 2.37-1.87 (brs, 1H).

1-(3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenyl)-4-(methylsulfonyl)piperidin-1-iummethanesulfonate (mesylate)

To a solution of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole(120 mg, 0.213 mmol) in DCM (2 mL) was added methanesulfonic acid (213μl, 0.213 mmol) and the resulting mixture was stirred at 50° C. for 1 h.The reaction mixture was allowed to cool to room temperature and thevolatiles were removed under reduced pressure. The solid was collected,triturated with ether (3×2 mL), and dried under reduced pressure to give1-(3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenyl)-4-(methylsulfonyl)piperidin-1-iummethanesulfonate (135 mg, 95%). ¹H NMR (600 MHz, CDCl₃) δ 8.31 (d, J=8.7Hz, 2H), 7.91-7.66 (brs, 1H), 7.60-7.47 (app brs, 2H), 7.40-7.30 (m,3H), 5.52 (s, 2H), 4.01-3.86 (app brs, 2H), 3.52-3.32 (app brs, 2H),3.31-3.18 (brs, 1H), 3.02 (s, 3H), 2.91 (s, 3H), 2.85-2.41 (m, 7H).

The trifluoroacetic acid salt was prepared in a similar manner to themesylate salt.

Additional Salt Preparation

Acetonitrile was selected as solvent system to prepare salts of Example80.

TABLE 1 Counter-ions used to prepare salts of4-Methanesulfonyl-1-{3-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-1,2,4-triazol-1-yl)methyl]phenyl}piperidine (Example 80)API/Acid No. Acids MW pKa (molar ratio) 1 HCl 36.46 −6 1:1 2 H₂SO₄ 98.08−3, 1.92 1:1 3 H₂SO₄ 98.08 −3, 1.92 2:1 4 CH₃SO₃H 96.10 −1.2 1:1 5p-toluenesulfonic acid 172.2 −1.34 1:1

Samples of Example 80 were dissolved in ACN at ambient laboratorytemperature. Appropriate amount of acids dissolved in correspondingsolvents were added to the samples according to 1:1 (or 1:2) molarratio. Additionally, Example 80 and solid acid (p-toluenesulfonic acid)were slurried (and in the case of Example 80, dissolved as well) in ACNindividually by stirring for 24 hrs, for use as XRPD controls.

The solids that precipitated out immediately after adding acids wereisolated by centrifugation and dried in a fume hood. Samples whichyielded no immediate precipitant were stirred at room temperature for 24hrs. After stirring for 24 hrs, solids precipitated from solution werealso isolated by centrifugation and dried in a fume hood. As for sampleswhich had no solids obtained after stifling 24 hrs, they were evaporatedby nitrogen to obtain solids.

Solid State Characterization of Solids Obtained in Counter-Ion Screen

Solids were visualized under a polarized light microscope (PLM) toconfirm the presence of crystals. Crystals were dried in fume hoodovernight then characterized by XRPD. In order to confirm the formedsolids are true salts instead of different polymorphs of the free base,the formed solids were compared with API control (Table 2, FIG. 11).

Based on the PLM and XRPD results (Table 2 and FIG. 11), no formtransformation was detected for API control (Example 80 free base).Samples obtained from HCl and CH₃SO₃H showed different XRPD pattern fromoriginal free base that indicate they may form the potential crystalsalts. The two potential crystal salts were further characterized tounderstand their physicochemical properties. Samples obtained from H₂SO₄with two ratios (1:1 and 2:1) and p-toluenesulfonic acid showedamorphous form.).

To confirm and obtain physicochemical properties of all the potentialcrystalline salts, further characterizations (DSC, TGA, NMR/ELSD, etc.)were conducted for the hydrochloride candidate and mesylate candidate(Table 2 and FIGS. 11-14).

For the hydrochloride candidate, DSC of hydrochloride candidate showsone typical endothermic peak at 164.0° C. (FIG. 12). TGA-MS profileshowed weight loss of ˜6.5% from 118.4° C. to 196.4° C. (FIG. 16), whichwas probably caused by water. Hydrochloride candidate could beclassified as slightly hygroscopic (1.59% weight gain from 0 to 80% RH)according to DVS result (FIG. 17). No form transformation was observedafter DVS test (FIG. 13). The molar ratio of chloride ion to free baseof the hydrochloride candidate is 0.98:1 based on ELSD results (Table2).

For the mesylate candidate the TGA profile showed weight loss of ˜1.7%from 91.5° C. to 193.1° C. and 3.8% from 93.1 to 216.6° C. (FIG. 18).The mesylate candidate decomposed at ˜190° C., and no obvious meltingpeak was found by DSC. The mesylate candidate could be classified ashygroscopic (2.47% weight gain from 0 to 80% RH) according to DVS result(FIG. 19). No form transformation was observed after DVS test (FIG. 15).

TABLE 2 Salt Experiment Results of Example 80 DSC Molar 1^(st) peak DVSratio XRPD (° C.)/ΔH TGA Sorption (ion:free No. Acids Pattern (J/g)Solid (wt. % loss) (%) base) 1 Free Base I 178.2/89.36 — 0.03 0.16 —(mp*¹) (171.5-182.9° C.) 2 CH₃SO₃H II No melting Light 1.67 2.47   1:1(1:1) peak Yellow (91.5-193.1° C.) observed 3.84 (193.1-216.6° C.) 3 HClIII 164.0/211.2 White 6.48 1.59 0.98:1 (1:1) (mp*¹) (118.4-196.4° C.) 4H₂SO₄ Amorphous — White — — — (1:1) 5 H₂SO₄ Amorphous Yellow — — — (2:1)6 p-toluene Amorphous — Light — — — sulfonic acid Yellow (1:1) *¹mpmeans the form showed a clear melting pointInstrument ParametersX-Ray Powder Diffractometer (XRPD)

Samples were run on XRPD (D8 Advance, Bruker) using the followingmethod: Tube: Cu: K-Alpha (λ=1.54179{acute over (Å)}). Generator:Voltage: 40 kV; Current: 40 mA. Scan Scope: 4 to 40 deg; Sample rotationspeed: 15 rpm. Scanning rate: 10 deg./min.

Differential Scanning Calorimetry (DSC) Methods

The DSC (Q2000, TA) method used the following conditions: Heat from 25°C. to 250° C. (300° C.) at 10° C./min

Thermal Gravimetric Analysis (TGA) Methods

The TGA (Q5000IR, TA) method used the following conditions: Heat from RTto 320° C. at 10° C./min.

Polarized Light Microscope (PLM)

The polarized light microscope method used the following equipment:Nikon LV100POL equipped with 5 megapixel CCD; Physical Lens: 20×/50×.

Dynamic Vapor Sorption (DVS)

Transfer about 10 mg of sample into a DVS (DVS Advantage-1, SMS) andrecord the weight change with respect to the atmospheric humidity at 25°C. Use the following parameters: Equilibrium: dm/dt: 0.01%/min. (formin: 10 min and max: 180 min). Drying: 0% RH for 120 min RH (%)measurement step: 10%; RH (%) measurement step scope: 0-90-0%

TABLE 4 Criteria for hygroscopicity evaluation HygroscopicityClassification Water Sorption Criterion* Deliquescent Sufficient wateris absorbed to form a Very hygroscopic ΔW % ≧ 15% Hygroscopic 15% > ΔW %≧ 2% Slightly hygroscopic 2% > ΔW % ≧ 0.2% Non-hygroscopic ΔW % < 0.2%*At 25 ± 1° C. and 80 ± 2% RH (European Pharmacopoeia 6.0)AssaysPK Analysis

Pharmacokinetic studies were performed in female CD-1 nude mice. —Either10 or 50 mg/kg of each test article was administered PO, QD in 0.5%methylcellulose aqueous solution or suspension. The compound5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolefree base was designated Group A;5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoletrifluoroacetic acid salt was designated Group B; and5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemesylate salt was designated Group C. Plasma concentrations wereanalyzed using a LC/MS method and the pharmacokinetic parameterscomputed using a noncompartmental method. Results are given below in thefollowing Tables (wherein BQL indicated the value was below the limit ofquantitation, SD is the standard deviation, and CV % is the coefficientof variation) and in FIG. 10. In CD-1 mice, plasma concentrations of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole2,2,2-trifluoroacetate and5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemethanesulfonate and5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolebesylate salt and5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride were significantly higher than that of the free base,5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole.It is expected that other compounds of the Formulas disclosed hereinwould have advantageous pharmacokinetic properties.

TABLE 5 Plasma Concentration in Female CD-1 Nude Mice Time Calc. Calc.Formulation Sample point Conc. Conc. Mean CV Group ID (h) (ng/mL) (nM)(nM) SD (%) A 1 2 160.4 285.4 561.2 179.6 32.0 A 2 2 369.5 657.3 A 3 2428.2 761.7 A 4 2 332.7 591.7 A 5 2 286.7 510.0 B 6 2 636.4 1131.9 834.8186.9 22.4 B 7 2 420.5 748.0 B 8 2 446.2 793.6 B 9 2 355.4 632.1 B 10 2488.1 868.2 C 11 2 1504.5 2676.0 2249.9 511.6 22.7 C 12 2 819.5 1457.7 C13 2 1532.2 2725.3 C 14 2 1264.1 2248.5 C 15 2 1204.2 2141.9 A 1 24555.0 987.2 414.3 325.2 78.5 A 2 24 172.7 307.2 A 3 24 192.7 342.7 A 424 131.2 233.3 A 5 24 113.1 201.3 B 6 24 802.0 1426.5 776.4 487.5 62.8 B7 24 124.1 220.7 B 8 24 627.5 1116.1 B 9 24 275.6 490.3 B 10 24 353.2628.2 C 1 8 h 1636.8 2911.4 N/A N/A N/A C 3 6 h 1659.5 2951.8 C 12 <24826.3 1469.8

TABLE 6 Group 1, Individual and mean plasma concentration-time data of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4- oxadiazoleFREE BASE after a PO dose of 10 mg/kg in fed female CD1 nude miceSampling Concentration (μM) Mean CV time (hr.) Individual (μM) SD (%) 0BQL BQL BQL BQL NA NA 0.083 0.02403 0.0121 0.0181 0.0181 0.00599 33.10.25 0.0865 0.0853 0.0795 0.0837 0.00375 4.48 0.5 0.230 0.419 0.2180.289 0.113 39.0 1 0.477 0.542 0.531 0.516 0.0346 6.70 2 0.670 0.4900.666 0.609 0.103 16.9 4 0.596 0.713 0.499 0.603 0.107 17.8 8 0.6240.478 0.599 0.567 0.0784 13.8 24 0.0991 0.0697 0.0974 0.0888 0.0165 18.6PK parameters Unit Estimated Value T_(max) hr. 2.00 C_(max) μM 0.609Terminal t_(1/2) hr. 6.83 AUC_(last) hr. * μM 9.61 AUC_(INF) hr. * μM10.5

TABLE 7 Group 2, Individual and mean plasma concentration-time data of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4- oxadiazoleFREE BASE after a PO dose of 10 mg/kg in fasted female CD1 nude miceSampling Concentration (μM) Mean CV time (hr.) Individual (μM) SD (%) 0BQL BQL BQL BQL NA NA 0.083 0.03472 0.0272 0.0248 0.0289 0.00516 17.90.25 0.216 0.315 0.309 0.280 0.0556 19.8 0.5 0.462 0.357 0.501 0.4400.0741 16.9 1 0.780 0.542 0.328 0.550 0.226 41.1 2 1.03 0.761 1.09 0.9590.174 18.1 4 0.646 0.608 0.704 0.652 0.0488 7.47 8 0.864 0.460 0.5580.627 0.211 33.6 24 0.324 0.155 0.199 0.226 0.088 38.7 PK parametersUnit Estimated Value T_(max) hr. 2.00 C_(max) μM 0.959 Terminal t_(1/2)hr. 12.4 AUC_(last) hr. * μM 12.1 AUC_(INF) hr. * μM 16.2

TABLE 8 Group 3, Individual and mean plasma concentration-time data of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4- oxadiazoleMESYLATE SALT after a PO dose of 10 mg/kg in female CD1 nude miceSampling Concentration (μM) Mean CV time (hr.) Individual (μM) SD (%) 0BQL BQL BQL BQL NA NA 0.083 0.0257 0.0222 0.0419 0.0299 0.0105 35.1 0.250.359 0.755 0.619 0.578 0.201 34.8 0.5 0.624 1.34 1.10 1.02 0.365 35.7 10.955 1.09 1.34 1.13 0.193 17.1 2 1.48 2.07 2.28 1.94 0.415 21.3 4 1.101.10 1.32 1.17 0.130 11.1 8 0.788 0.784 1.23 0.934 0.256 27.4 24 0.3960.287 0.349 0.344 0.0544 15.8 PK parameters Unit Estimated Value T_(max)hr. 2.00 C_(max) μM 1.94 Terminal t_(1/2) hr. 11.2 AUC_(last) hr. * μM19.9 AUC_(INF) hr. * μM 25.5

TABLE 9 Group 4, Individual and mean plasma concentration-time data of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4- oxadiazoleBESYLATE SALT after a PO dose of 10 mg/kg in female CD1 nude miceSampling Concentration (μM) Mean CV time (hr.) Individual (μM) SD (%) 0BQL BQL BQL BQL NA NA 0.083 0.00724 0.00741 0.00527 0.00664 0.00119 17.90.25 0.104 0.159 0.147 0.137 0.0292 21.4 0.5 0.877 0.849 0.660 0.7950.118 14.8 1 0.591 0.849 0.683 0.708 0.131 18.5 2 0.599 0.947 0.8710.805 0.183 22.7 4 1.02 1.03 1.09 1.05 0.0397 3.79 8 0.436 0.586 0.5220.515 0.0749 14.6 24 0.222 0.185 0.245 0.217 0.0306 14.1 PK parametersUnit Estimated Value T_(max) hr. 4.00 C_(max) μM 1.05 Terminal t_(1/2)hr. 9.69 AUC_(last) hr. * μM 12.1 AUC_(INF) hr. * μM 15.1

TABLE 10 Group 5, Individual and mean plasma concentration-time data of5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4- oxadiazoleHYDROCHLORIDE SALT after a PO dose of 10 mg/kg in female CD1 nude miceSampling Concentration (μM) Mean CV time (hr.) Individual (μM) SD (%) 0BQL BQL BQL BQL NA NA 0.083 0.821 0.242 0.258 0.440 0.330 74.9 0.25 4.761.43 3.25 3.15 1.66 52.9 0.5 5.95 4.07 2.62 4.21 1.67 39.7 1 6.65 3.445.87 5.32 1.67 31.4 2 5.88 1.72 3.02 3.54 2.13 60.1 4 4.30 4.06 2.743.70 0.839 22.7 8 2.15 4.03 1.67 2.61 1.25 47.7 24 0.553 0.541 0.5030.532 0.0257 4.83 PK parameters Unit Estimated Value T_(max) hr. 1.00C_(max) μM 5.32 Terminal t_(1/2) hr. 7.09 AUC_(last) hr. * μM 53.1AUC_(INF) hr. * μM 58.5Cell-Based Reporter Assay for IC₅₀ Determinations

293T-HRE-GFP-luc cells were routinely maintained in DMEM media (highglucose version with GlutaMAX and HEPES, Gibco, catalog #10564)supplemented with 10% fetal bovine serum and 2 μg/mL puromycin(Invitrogen, catalog #A11138-03) using a humidified incubator (normoxicconditions consisting of 37° C., 5% CO₂ and ambient O₂).

In preparation for the reporter assay, cells were harvested andresuspended in DMEM media (high glucose version with GlutaMAX and HEPES)supplemented with 10% fetal bovine serum. Cells were inoculated into384-well white Culturplates (Perkin Elmer catalog #6007680) at a densityof 12,000 cells/well in a volume of 30 μL. The microplates wereincubated overnight (approximately 17-19 hours) at 37° C. with 5% CO₂and ambient 02. Stock solutions of the test compounds were prepared inDMSO (Sigma, Catalog #D2650) and serially diluted 1:3 using DMSO.Compounds were additionally diluted (1:50) with culture medium and 10 μLwere added per well to the Culturplate. Following a 30 min. incubationunder normoxic conditions, the plates were incubated in hypoxia for 6hrs. (37° C., 5% CO₂ and 1% O₂). Steadylite Plus (Perkin Elmer, catalog#6016751) was then added (40 μL/well), the plates were mixed on anorbital shaker at room temperature in the dark for 15 min., andluminescence was measured using an Envision plate reader (Perkin Elmer).IC₅₀ values were calculated using a four-parameter logistic curve fit.Results are shown below in Table 11; ND indicates no data.

TABLE 11 Classification: A = <100 nM B = 100-1000 nM Example No. C =1-10 uM 80 ADiffuse Large B-Cell Lymphoma (DLBCL) Assay

Equal number of TMD8 cells were plated and treated with varyingconcentrations of the compound of Example 80 for 7 days. Percent ofviable cells was determined using Guava ViaCount reagents (EMD Milliporecat #4000-0040) that contains proprietary dyes that enable thedetermination of the number of live and dead cells in a sample (FIG. 1).TMD8 cells respond robustly to the compound of Example 80, indicatingthe effectiveness of the compound as an anti-tumor agent in DLBCL.

Acute Myeloid Leukemia

The OCI-AML3 cell line was treated with various concentrations ofcompound for 2 days and the percent of viable cells normalized tocontrol cells treated with DMSO (FIG. 6). OCI-AML3 cells constitutivelyexpressing luciferase were tail vein injected in NSG nude mice. 17 daysafter cell injection, luciferin was injected into animals and luciferasesignal was measured using an IVIS imaging system to determine tumorburden and for randomization of subjects into study groups. On day 18,animals began receiving daily oral doses of vehicle or 10 mpk of thecompound of Example 80 which continued throughout the study. On day 28,imaging was performed again to determine tumor burden (FIG. 7).Treatment of tumor cell bearing animals with the compound of Example 80significantly increased their survival relative to vehicle treatedanimals (FIG. 8).

Neuroblastoma and Glioblastoma Cellular Assay and Xenograft Model

Cellular Assays:

NB-1, Gli56, and D423 cell lines are deleted for ENO-1 (GLI56 and D423)or PGD, which renders them with reduced glycolytic capacity (Muller, F.et al., Nature, 2012, 488, 337-42). When these cell lines are treatedwith various concentrations of Example 80, cell numbers aresignificantly reduced with cell death readily apparent in NB-1 and Gli56(FIG. 2-4).

Xenograft Model:

To establish activity and provide in vivo proof of concept, NB-1 cellswere implanted into CD-1 nude mice and treated with 40 mpk of thecompound of Example 80 po or vehicle daily when tumors reached 400-500mm³. Tumor size was measured 3×/week using caliper measurements (FIG.5).

In Vivo Murine Xenograft Models for Tumor Growth Inhibition

The compounds disclosed herein have been evaluated in vivo and shown toinhibit the growth of human cancer xenografts in nude mice.

Non-Small Cell Lung Cancer:

H₄₆₀ cells may be implanted subcutaneously in CD-1 nude mice and treatedwith 150 mpk qdx14 PO of a compound disclosed herein delivered by oralgavage for 14 days. Animals are randomized into study groups and thestudy initiated when the average tumor volume is 400 mm³. Duringtreatment, tumor volume is measured three times per week to determinetumor growth over the course of the study. On day 15, 3 hours prior totake down, hypoxyprobe (Hypoxyprobe, Inc. cat # HP3) is injected intomice. Tumor sections are stained (dark areas) for the level of hypoxiautilizing an anti-hypoxyprobe antibody and standard IHC methods. Thesame tumors are stained for the expression of HIF regulated genecarbonic anhydrase IX (CA9) using standard IHC methods. Treatment of themice with a free base of a compound disclosed herein has been shown toinhibit the growth of the H460 xenografts over the course of the study,establishing the anti-tumor activity of the compound like thosedescribed herein. Target engagement, as measured by elimination ofhypoxia and CA9 protein expression in the tumor, was achievedestablishing that at the anti-tumor activity level, the compound isinhibiting HIF pathway activity. It is expected that the compoundsdisclosed herein will be similarly efficacious and in some cases moreefficacious.

Head and Neck Cancer:

In one example of an in vivo study, HN5 head and neck cells are injectedintramuscularly into CD-1 nude mice. Upon tumors reaching 8.5 mm indiameter, animals are enrolled in the study and received either vehicleor test compound with or without a 4 Gy dose 6 hours after test compoundon days 1-5 of the study. Tumor size is measured every other day todetermine the rate of growth.

Further examples of xenograft models are given below for glioblastomacancer.

Glioblastoma Cancer.

In one example of a typical protocol, female athymic nu/nu nude mice, 5to 6 weeks-old (approx. 18-22 g) may be obtained, for example fromHarland Sprague-Dawley, Inc. Nude mice are inoculated with tumor cells.U251, U87-EGFRviii or other human cancer cells, at a concentration ofabout 1-5×10⁶ in 0.15 ml solution mixed with matrigel and DMEM mediumare injected subcutaneously into the right flank of each mouse. Whentumor volume reaches around 200 or 600 mm³, animal are randomly assignedto three groups (or more, depending on the number of dose levels of acompound to be evaluated) and treatment started with test article (forexample, at 5 mg/kg/day or 10 mg/kg/day) delivered via oral gavage forup to 21 days. Animals in control group receive the vehicle alone underidentical conditions. Tumor volumes are measured by a digital caliperand calculated using the formula (L×W×H)×0.5236. Significant differencesare expected to be observed compared with control group (P<0.05, usingANOVA). Animal weight is monitored throughout the experiment. It isexpected that no significant difference will be observed between controland treated groups, which further indicates the test article isnon-toxic in tumor-bearing nude mice at doses used for inhibiting tumorgrowth.

The foregoing protocols are versatile, and may be modified to substitutevirtually any type of human cancer cell line. Examples include thebreast cancer cell lines AG11132A, MCF-7, and T47-D; estrogen,progesterone, and HER-2/neu receptor positive breast cancer cell linesHCC-1428 and ZR-75; estrogen, progesterone, and HER-2/neu receptorsnegative breast cancer cell lines MDA-231 and BT20; prostate cancer celllines LNCaP, PC-3, and DU145; colon cancer cell lines DLD-1 and LoVo;ovarian cancer cell lines OVCAR-3 and SK-OV-3; lung cancer cell linesH69AR, NCI-H23, and A549; and pancreatic cancer cell lines Capan-1 andBxPC-3. Additionally, the protocol may be altered to assay theprevention of tumor development by pre-treating with test compound.Combinations of compounds may be tested, and dosing schedules altered todeliver compound in other ways, i.e., by oral gavage, or to skip days oftreatment to reduce any toxic signals. Those skilled in the art willrecognize and appropriately apply the multitude of variations available.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present disclosure. However, thedisclosure described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the disclosure. Anyequivalent embodiments are intended to be within the scope of thisdisclosure. Indeed, various modifications of the disclosure in additionto those shown and described herein will become apparent to thoseskilled in the art from the foregoing description, which do not departfrom the spirit or scope of the present inventive discovery. Suchmodifications are also intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A compound of structural Formula III:

wherein: M is selected from the group consisting of an inorganic acidand an organic acid; with the proviso that M is not trifluoroaceticacid; a is a fractional or whole number between about 0.5 and about 3.5inclusive; b is a fractional or whole number between about 0 and about10 inclusive; X₂ and X₄ are N and X₅ is O; X₄ and X₅ are N and X₂ is O;X₂ and X₅ are N and X₄ is O; X₂ is CH, X₄ is N, and X₅ is O; or X₂ isCH, X₄ is O, and X₅ is N; Z₂ is selected from the group consisting of Nand CR₁₄; R₁ is selected from the group consisting of heterocycloalkyl,alkoxyalkoxy, alkylsulfonylalkoxy, heterocycloalkyloxy,heterocycloalkylcarbonyl, alkoxyalkylamido, heterocycloalkylsulfonyl,alkoxyalkylsulfonamido, wherein said heterocycloalkyl,heterocycloalkyloxy, heterocycloalkylcarbonyl, andheterocycloalkylsulfonyl is optionally substituted with one or moresubstituents selected from the group consisting hydrogen, alkyl, andoxo; R₁₄, R₃₉, and R₄₀ are independently selected from the groupconsisting of hydrogen, deuterium, halogen, alkyl, haloalkyl,perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy,alkylthio, amino, and saturated 3- to 7-membered cycloalkyl, any ofwhich is optionally substituted; and R₁₈ is selected from the groupconsisting of alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy,perhaloalkoxy, alkylthio, haloalkylthio, and perhaloalkylthio.
 2. Thecompound as recited in claim 1 wherein R₁ is selected from the groupconsisting of


3. The compound as recited in claim 1 wherein R₁₈ is selected from thegroup consisting of isopropyl, tert-butyl, —CF₃, —OCF₃, —OCHF₂, and—SCF₃.
 4. The compound as recited in claim 1 wherein: R₁ is selectedfrom the group consisting of

R₁₃, R₁₄, R₁₆, R₁₇, and R₁₉ are hydrogen; and R₁₈ is selected from thegroup consisting of isopropyl, tert-butyl, —CF₃, —OCF₃, —OCHF₂, and—SCF₃.
 5. The compound of claim 1, wherein the compound is in a solidform.
 6. The compound of claim 1, wherein the compound is in acrystalline form.
 7. The compound of claim 1, wherein M is selected fromthe group consisting of (+)-camphor-10-sulfonic acid, 2,2-dichloroaceticacid, 2-hydroxyethanesulfonic acid, acetic acid, aspartic acid,benzenesulfonic acid, citric acid, cyclamic acid, di(tert-butyl)naphthalenesulfonic acid, dodecylsulfonic acid, ethanesulfonic acid,formic acid, fumaric acid, glutamic acid, glycerophosphoric acid,glycine, hydroboric acid, hydrobromic acid, hydrochloric acid, lacticacid, maleic acid, malic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, nitric acid, oxalic acid, phosphoric acid,p-toluenesulfonic acid, pyruvic acid, saccharine, succinic acid,sulfuric acid, tartaric acid, and thiocyanic acid.
 8. The compound ofclaim 1, wherein M is selected from the group consisting of hydrochloricacid, benzenesulfonic acid, and methanesulfonic acid.
 9. The compound ofclaim 1, wherein a equals 1 and M is hydrochloric acid.
 10. The compoundof claim 1, wherein a equals 1 and M is benzenesulfonic acid.
 11. Thecompound of claim 1, wherein a equals 1 and M is methanesulfonic acid.12. The compound of claim 1, wherein the compound has structural FormulaV

wherein M is selected from the group consisting of(+)-camphor-10-sulfonic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, acetic acid, aspartic acid,benzenesulfonic acid, citric acid, cyclamic acid, di(tert-butyl)naphthalenesulfonic acid, dodecylsulfonic acid, ethanesulfonic acid,formic acid, fumaric acid, glutamic acid, glycerophosphoric acid,glycine, hydroboric acid, hydrobromic acid, hydrochloric acid, lacticacid, maleic acid, malic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, nitric acid, oxalic acid, phosphoric acid,p-toluenesulfonic acid, pyruvic acid, saccharine, succinic acid,sulfuric acid, tartaric acid, and thiocyanic acid; a is a fractional orwhole number between about 0.5 and about 3.5 inclusive; and b is afractional or whole number between about 0 and about 5 inclusive.
 13. Acompound of Formula V

wherein M is selected from the group consisting of hydrochloric acid,di(tert-butyl) naphthalenesulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic acid, cyclamic acid, p-toluenesulfonic acid,thiocyanic acid, nitric acid, methanesulfonic acid, dodecylsulfonicacid, naphthalene-2-sulfonic acid, benzenesulfonic acid, oxalic acid,saccharine, 2,2-dichloroacetic acid, glycerophosphoric acid, phosphoricacid, (+)-camphor-10-sulfonic acid, sulfuric acid, maleic acid, andpyruvic acid; a is a fractional or whole number between about 0.5 andabout 3.5 inclusive; and b is a fractional or whole number between about0 and about 5 inclusive.
 14. The compound of claim 13, wherein M ischosen from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid,nitric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid,and maleic acid.
 15. The compound of claim 14, wherein M is chosen fromhydrochloric acid, methanesulfonic acid, and benzenesulfonic acid. 16.The compound of claim 13, wherein: a is a number between 1 and 2inclusive; and b is a number between 0 and about 2 inclusive.
 17. Thecompound of claim 13, wherein a equals 1, and M is hydrochloric acid.18. The compound of claim 13, wherein a equals 1 and M isbenzenesulfonic acid.
 19. The compound of claim 13, wherein a equals 1and M is methanesulfonic acid.
 20. A compound of Formula VI

wherein X is chosen from chloride, di(tert-butyl) naphthalenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, cyclamate, tosylate,thiocyanate, nitrate, mesylate, dodecylsulfonate,naphthalene-2-sulfonate, besylate, oxalate, saccharate,2,2-dichloroacetate, glycerophosphorate, phosphorate,(+)-camphor-10-sulfonate, maleate, sulfate, and pyruvate.
 21. Thecompound of claim 20, wherein X is chosen from chloride, sulfate,tosylate, nitrate, mesylate, besylate, and maleate.
 22. The compound ofclaim 20, wherein X is chosen from chloride, mesylate, and besylate. 23.A compound selected from the group consisting of:5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride;5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole2,2,2-trifluoroacetate;5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemethanesulfonate; and5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolebenzenesulfonate.
 24. A pharmaceutical composition comprising a compoundas recited in claim 1 together with a pharmaceutically acceptablecarrier.
 25. The compound5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolehydrochloride.
 26. A pharmaceutical composition comprising the compoundas recited in claim 25 together with a pharmaceutically acceptablecarrier.
 27. The compound5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolemethanesulfonate.
 28. A pharmaceutical composition comprising thecompound as recited in claim 27 together with a pharmaceuticallyacceptable carrier.
 29. The compound5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazolebenzenesulfonate.
 30. A pharmaceutical composition comprising thecompound as recited in claim 29 together with a pharmaceuticallyacceptable carrier.